Enantioselective cross dehydrogenative coupling reactions and compounds synthesized by the reactions

ABSTRACT

Disclosed are enantioselective cross dehydrogenative coupling reactions for synthesizing tetrahydropyran compounds. Novel tetrahydropyran compounds may be synthesized by the disclosed methods as well as tetrahydropyran precursor compounds for synthesizing various naturally occurring compounds. The enantioselective cross dehydrogenative coupling reactions utilize in situ Lewis Acid activation in combination with oxidative formation of an oxocarbenium ion to provide a highly efficient and selective coupling reaction for synthesizing tetrahydropyran compounds.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a continuation of U.S. patent application Ser. No. 16/710,512, filed on Dec. 11, 2019, now U.S. Pat. No. 11,174,238, and claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62/778,016, filed on Dec. 11, 2018, of which the content of each is incorporated herein by reference in their entireties.

BACKGROUND

The field of the invention relates to tetrahydropyran compounds and methods for synthesizing tetrahydropyran compounds. In particular, the field of the invention relates to enantioselective cross dehydrogenative coupling reactions for synthesizing tetrahydropyran compounds

Tetrahydropyrans (THPs) are key structural elements in numerous bioactive natural products and medicinally relevant compounds.¹ Due to the prevalence of THPs, multiple stereoselective processes have been developed for their construction, including Prins cyclizations,² hetero-Diels-Alder reactions,³ and intramolecular nucleophilic conjugate additions.⁴ Established methods to construct THPs in an enantioselective fashion typically focus on conjugate additions⁵ or activation by enamine/iminium intermediates,⁶ two approaches that are deployed extensively in total synthesis. Inspired by natural product targets of interest in our laboratory, as well as small molecules possessing intriguing biological activity, we envisioned a complementary and direct method for the enantioselective synthesis of substituted tetrahydropyran-4-ones. The inventors have disclosed the use of β-hydroxy dioxinones as nucleophiles with aldehydes and isatins to undergo mild and stereoselective cyclizations in the presence of catalytic Lewis or Brønsted acids to access enantioenriched THPs.⁷ The inventors' efforts in this area have enabled total syntheses of various natural products including exiguolide,⁸ neopeltolide,⁹ okilactomycin,¹⁰ and other naturally occurring compounds containing THPs.¹¹ Conceptually, moving beyond preformed nucleophiles such as dioxinones to simple β-ketoester systems presents opportunities for enantiocontrol, most likely through two-point/chelate binding, but also requires different activation modes to operate simultaneously in a single reaction flask.

Here, the inventors disclose an enantioselective cross-dehydrogenative coupling (CDC) reaction which may be utilized to prepare tetrahydropyrans and derivatives thereof. The disclosed CDC reaction combines in situ Lewis acid activation of a nucleophile together with the oxidative formation of a transient oxocarbenium electrophile, which leads to a productive and highly enantioselective CDC reaction. The disclosed CDC reaction represents one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. The disclosed CDC reactions may be utilized to access valuable tetrahydropyran motifs found in many natural products and bioactive small molecules.

SUMMARY

Disclosed are enantioselective cross dehydrogenative coupling reactions for synthesizing tetrahydropyran compounds. Novel tetrahydropyran compounds may be synthesized by the disclosed methods as well as tetrahydropyran precursor compounds for synthesizing various naturally occurring compounds. The enantioselective cross dehydrogenative coupling reactions utilize in situ Lewis Acid activation in combination with oxidative formation of an oxocarbenium ion to provide a highly efficient and selective coupling reaction for synthesizing tetrahydropyran compounds.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 . Stereochemical induction model with 1a/(2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) intermediate.

FIG. 2 . ORTEP representation (50% probability) of the crystal structure of 2h.

FIG. 3 . PM3 optimized structure of L3.Cu(II) with 1a/(2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) intermediate.

FIG. 4 . PM3 optimized structure of L3.Cu(II)(H₂O)₂.

FIG. 5 . CDC Processes and Reaction Design.

DETAILED DESCRIPTION

The disclosed subject matter further may be described utilizing terms as defined below.

Unless otherwise specified or indicated by context, the terms “a”, “an”, and “the” mean “one or more.” For example, “a compound” should be interpreted to mean “one or more compounds.”

As used herein, “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean plus or minus ≤10% of the particular term and “substantially” and “significantly” will mean plus or minus >10% of the particular term.

As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.

New Chemical Entities and Methods of Synthesis

New chemical entities and uses for chemical entities are disclosed herein. The chemical entities may be described using terminology known in the art and further discussed below.

As used herein, an asterisk “*” or a plus sign “+” may be used to designate the point of attachment for any radical group or substituent group.

The term “alkyl” as contemplated herein includes a straight-chain or branched alkyl radical in all of its isomeric forms, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively.

The term “alkylene” refers to a diradical of an alkyl group (e.g., —(CH₂)_(n)— where n is an integer such as an integer between 1 and 20). An exemplary alkylene group is —CH₂CH₂—.

The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃, and the like.

The term “heteroalkyl” as used herein refers to an “alkyl” group in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). One type of heteroalkyl group is an “alkoxy” group.

The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively.

The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkynyl, C2-C10-alkynyl, and C2-C6-alkynyl, respectively.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C4-8-cycloalkyl,” derived from a cycloalkane. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halo, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted.

The term “cycloalkylene” refers to a cycloalkyl group that is unsaturated at one or more ring bonds.

The term “partially unsaturated carbocyclyl” refers to a monovalent cyclic hydrocarbon that contains at least one double bond between ring atoms where at least one ring of the carbocyclyl is not aromatic. The partially unsaturated carbocyclyl may be characterized according to the number of ring carbon atoms. For example, the partially unsaturated carbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and accordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclyl, respectively. The partially unsaturated carbocyclyl may be in the form of a monocyclic carbocycle, bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle, spirocyclic carbocycle, or other carbocyclic ring system. Exemplary partially unsaturated carbocyclyl groups include cycloalkenyl groups and bicyclic carbocyclyl groups that are partially unsaturated. Unless specified otherwise, partially unsaturated carbocyclyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted.

The term “aryl” is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term “aryl” includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unless specified otherwise, the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. In certain embodiments, the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the aromatic ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in the heterocyclyl group can be specified using 5 Cx-Cx nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-C7 heterocyclyl group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The designation “C3-C7” indicates that the heterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines (e.g., mono-substituted amines or di-substituted amines), wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl.

The terms “alkoxy” or “alkoxyl” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, tert-butoxy and the like.

An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, and the like.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “oxo” refers to a divalent oxygen atom —O—.

The term “carboxamido” as used herein refers to the radical —C(O)NRR′, where R and R′ may be the same or different. R and R′, for example, may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl.

The term “carboxy” as used herein refers to the radical —COOH or its corresponding salts, e.g. —COONa, etc.

The term “amide” or “amido” or “amidyl” as used herein refers to a radical of the form —R¹C(O)N(R²)—, —R¹C(O)N(R²)R³—, —C(O)NR²R³, or —C(O)NH₂, wherein R¹, R² and R³, for example, are each independently alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.

The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” or “+” or “−” depending on the configuration of substituents around the stereogenic carbon atom and or the optical rotation observed. The present invention encompasses various stereo isomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated (±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise. Also contemplated herein are compositions comprising, consisting essentially of, or consisting of an enantiopure compound, which composition may comprise, consist essential of, or consist of at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of a given compound (e.g., at least about 99% of an R enantiomer of a given compound).

Enantioselective Cross Dehydrogenative Coupling Reactions and Compounds Synthesized the Reactions

The subject matter of the application relates to enantioselective cross dehydrogenative coupling reactions for synthesizing tetrahydropyran compounds. Novel tetrahydropyran compounds may be synthesized by the disclosed methods as well as tetrahydropyran precursor compounds for synthesizing various natural occurring compounds.

In some embodiments, the disclosed compounds may have Formula I or a tautomer thereof:

where: X is hydrogen or alkyl (e.g. methyl); n is 0-6; R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or aryl, optionally wherein R¹ is a single 5-membered or 6-membered ring or two or more fused 5-membered or 6-membered rings, wherein the single ring or two or more fused rings are carbocyclic or heterocyclic rings containing one or more heteroatoms selected from N, O, and S, and wherein the ring or two or more fused rings are saturated or unsaturated at one or more bonds, optionally wherein the single ring or more fused rings are substituted at one or more positions with a substituent selected from alkyl, alkoxy, halo, amino, and cyano; R² is hydrogen, alkyl, aryl,

wherein R⁸ is hydrogen, alkyl, or aryl; R³ is hydrogen, hydroxyl, or oxo; R⁴ is hydrogen or alkyl; and R⁵ is hydrogen or

R⁶ is hydrogen, hydroxyl, or oxo; and R⁷ is hydrogen or alkyl.

In some embodiments of the disclosed compounds, n is 0-2 and R¹ is selected from phenyl (optionally substituted at one or more positions with alkyl, alkoxy (e.g., 4-methoxy, 3,4-dimethoxy, or 3,4,5-trimethoxy), halo, or haloalkyl (e.g., trifluoromethyl)), naphthyl (e.g., naphth-1-yl or naphtha-2-yl), indolyl (e.g., indol-3-yl), thiazolyl (e.g., thiazol-2-yl).

In some embodiments, disclosed compounds may have a formula selected from:

In some embodiments, the disclosed compounds may have a formula selected from:

In some embodiments, the disclosed compounds may be utilized, for example as precursors, to prepare naturally occurring or man-made products. Naturally occurring products that may be prepared using the disclosed compounds include, but are not limited to exiguolide, neopeltolide, and okilactomycin and other compounds that contain tetrahydropyrans. (See, e.g., Crane, E. A.; Zabawa, T. P.; Farmer, R. L.; Scheidt, K. A. Angew. Chem. Int. Ed. 2011, 50, 9112-9115; Custar, D. W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 12406-12414; Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 804-805; Tenenbaum, J. M.; Morris, W. J.; Custar, D. W.; Scheidt, K. A. Angew. Chem. Int. Ed. 2011, 50, 5892-5895; Lee, K.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 2722-2725; Lee, K.; Kim, H.; Hong, J. Angew. Chem. Int. Ed. 2012, 51, 5735-5738; Han, X.; Peh, G.; Floreancig, P. E. Eur. J. Org. Chem. 2013, 2013, 1193-1208; and Nasir, N. M.; Ermanis, K.; Clarke, P. A. Org. Biomol. Chem. 2014, 12, 3323-3335; the contents of which are incorporated herein by reference in their entireties.

In some embodiments, the disclosed compounds or pharmaceutical salts or hydrates thereof may be formulated as pharmaceutical composition. For example, the disclosed compounds or pharmaceutical salts or hydrates thereof may be formulated together with a pharmaceutical carrier to prepare a pharmaceutical composition.

Also disclosed herein are novel complexes. In some embodiments, the disclosed complexes have a formula represented as L.M²⁺(OTf)₂, wherein M is a divalent metal such as Cu(II), Tf is triflyl, and L has a formula:

where R⁹ and R^(9′) together form a 3-membered, 4-membered, 5-membered, or 6-membered carbocyclic ring; and R¹⁰ and R¹¹ are alkyl (e.g., n-butyl).

In some embodiments of the disclosed complexes, L may have a formula selected from:

The compounds disclosed herein may be prepared by methods that include, but are not limited to a method comprising reacting a mixture comprising:

-   (a) a compound having a formula

-   -   wherein:     -   X is hydrogen or alkyl (e.g. methyl);     -   n is 0-6;     -   R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or aryl,         optionally wherein R¹ is a single 5-membered or 6-membered ring         or two or more fused 5-membered or 6-membered rings, wherein the         single ring or two or more fused rings are carbocyclic or         heterocyclic rings containing one or more heteroatoms selected         from N, O, and S, and wherein the ring or two or more fused         rings are saturated or unsaturated at one or more bonds,         optionally wherein the single ring or more fused rings are         substituted at one or more positions with a substituent selected         from alkyl, alkoxy, halo, amino, and cyano; and     -   R⁷ is hydrogen or alkyl;

-   (b) a complex having a formula L.M²⁺(OTf)₂, wherein M is a divalent     metal (e.g., such as Cu(II)), Tf is triflyl, and L has a formula:

-   -   wherein R⁹ and R¹⁰ are independently selected from alkyl,         phenyl, or R⁹ and R^(9′) together form a 3-membered, 4-membered,         5-membered, or 6-membered carbocylic ring; and     -   R¹⁰ and R¹¹ are alkyl (e.g., n-butyl);     -   optionally wherein L has a formula selected from:

-   (c) an oxidant (optionally wherein the oxidant is     (2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)); and

optionally

-   (d) a salt (optionally wherein the salt is a sodium salt such as a     sodium phosphate salt such as disodium phosphate).

In some embodiments of the disclosed reactions, the reaction mixture may be prepared using a solvent. Suitable solvents may include but are not limited to halogenated alkanes such as dichloromethane.

In some embodiments of the disclosed reactions, the reaction may be performed at a relatively low temperature. Suitable temperatures for performing the disclosed reactions may include temperatures of less than about 0, ⁻10, ⁻20, ⁻30, ⁻40, ⁻50, ⁻60, ⁻70, ⁻80, ⁻90, or ⁻100° C. or a temperature range bounded by any of these values (e.g., ⁻50-⁻90° C.).

In some embodiments of the disclosed reactions, the reaction may be performed utilizing a molecular sieve (MS). In some embodiments, the MS has an average effective pore diameter of less than about 20, 10, 8, 6, 4, or 2 angstroms (Å) or a diameter range bounded by any of these values (e.g., 2-6 Å).

As noted, the compounds disclosed herein may have several chiral centers, and stereoisomers, epimers, and enantiomers are contemplated. The compounds may be optically pure with respect to one or more chiral centers (e.g., some or all of the chiral centers may be completely in the S configuration; some or all of the chiral centers may be completely in the R configuration; etc.). Additionally or alternatively, one or more of the chiral centers may be present as a mixture of configurations (e.g., a racemic or another mixture of the R configuration and the S configuration). Compositions comprising substantially purified stereoisomers, epimers, or enantiomers, or analogs or derivatives thereof are contemplated herein (e.g., a composition comprising at least about 90%, 95%, 99% or 100% pure stereoisomer, epimer, or enantiomer.) As used herein, formulae which do not specify the orientation at one or more chiral centers are meant to encompass all orientations and mixtures thereof.

ILLUSTRATIVE EMBODIMENTS

The following embodiments are illustrative and should not be interpreted to limit the scope of the claimed subject matter.

Embodiment 1. A compound having Formula I or a tautomer thereof:

wherein:

-   X is hydrogen or alkyl (e.g. methyl); -   n is 0-6; -   R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or aryl,     optionally wherein R¹ is a single 5-membered or 6-membered ring or     two or more fused 5-membered or 6-membered rings, wherein the single     ring or two or more fused rings are carbocyclic or heterocyclic     rings containing one or more heteroatoms selected from N, O, and S,     and wherein the ring or two or more fused rings are saturated or     unsaturated at one or more bonds, optionally wherein the single ring     or more fused rings are substituted at one or more positions with a     substituent selected from alkyl, alkoxy, halo, amino, and cyano; -   R² is hydrogen, alkyl, aryl,

wherein R⁸ is hydrogen, alkyl, or aryl;

-   R³ is hydrogen, hydroxyl, or oxo; -   R⁴ is hydrogen or alkyl; -   R⁵ is hydrogen or

-   R⁶ is hydrogen, hydroxyl, or oxo; and -   R⁷ is hydrogen or alkyl.

Embodiment 2. The compound of embodiment 1 having a Formula I(a) or a tautomer thereof:

Embodiment 3. The compound of embodiment 1 having a Formula I(b) or a tautomer thereof:

Embodiment 4. The compound of embodiment 1 having a Formula Ic or a tautomer thereof:

Embodiment 5. The compound of embodiment 1 having a Formula Id or a tautomer thereof:

Embodiment 6. The compound of embodiment 1 having a Formula I(e) or a tautomer thereof:

Embodiment 7. The compound of embodiment 1, wherein n is 0-2 and R¹ is selected from phenyl (optionally substituted at one or more positions with alkyl, alkoxy (e.g., 4-methoxy, 3,4-dimethoxy, or 3,4,5-trimethoxy), halo, or haloalkyl (e.g., trifluoromethyl)), naphthyl (e.g., naphth-1-yl or naphtha-2-yl), indolyl (e.g., indol-3-yl), thiazolyl (e.g., thiazol-2-yl).

Embodiment 8. The compound of embodiment 1 having a Formula I(f):

Embodiment 9. The compound of embodiment 1 having a Formula I(g):

Embodiment 10. The compound of embodiment 1 having a Formula I(h) or a tautomer thereof:

Embodiment 11. The compound of embodiment 1 having a Formula I(i) or a tautomer thereof:

Embodiment 12. The compound of embodiment 1 having a Formula I(j):

Embodiment 13. The compound of embodiment 1 having a Formula I(k) or a tautomer thereof:

Embodiment 14. The compound of embodiment 1 having a Formula I(l) or a tautomer thereof:

Embodiment 15. The compound of any of the foregoing embodiments having a formula selected from:

Embodiment 16. A pharmaceutical composition comprising any of the compounds of the foregoing embodiments or a pharmaceutical salt or hydrate thereof together with a pharmaceutical carrier.

Embodiment 17. A complex having a formula represented as L.M²⁺(OTf)₂, wherein M is a divalent metal (e.g., Cu(II)), Tf is triflyl, and L has a formula:

Wherein:

-   R⁹ and R^(9′) together form a 3-membered, 4-membered, 5-membered, or     6-membered carbocyclic ring; and -   R¹⁰ and R¹¹ are alkyl (e.g., n-butyl).

Embodiment 18. The complex of embodiment 17, wherein L has a formula:

Embodiment 19. The complex of embodiment 17, wherein L has a formula:

Embodiment 20. The complex of embodiment 17, wherein L has a formula:

Embodiment 21. The complex of embodiment 17, wherein L has a formula:

Embodiment 22. A method for preparing any of the compounds of embodiments 1-15, the method comprising reacting a mixture comprising:

-   -   (a) a compound having a formula

-   -   -   wherein:         -   X is hydrogen or alkyl (e.g. methyl)         -   n is 0-6;         -   R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or             aryl, optionally wherein R¹ is a single 5-membered or             6-membered ring or two or more fused 5-membered or             6-membered rings, wherein the single ring or two or more             fused rings are carbocyclic or heterocyclic rings containing             one or more heteroatoms selected from N, O, and S, and             wherein the ring or two or more fused rings are saturated or             unsaturated at one or more bonds, optionally wherein the             single ring or more fused rings are substituted at one or             more positions with a substituent selected from alkyl,             alkoxy, halo, amino, and cyano; and         -   R⁷ is hydrogen or alkyl;

    -   (b) a complex having a formula L.M²⁺(OTf)₂, wherein M is a         divalent metal, Tf is triflyl, and L has a formula:

-   -   -   wherein:         -   R⁹ and R^(9′) are independently selected from alkyl, phenyl,             or R⁹ and R^(9′) together form a 3-membered, 4-membered,             5-membered, or 6-membered carbocylic ring; and         -   R¹⁰ and R¹¹ are alkyl (e.g., n-butyl);         -   optionally wherein the complex is the complex of any of             embodiments 16-20;

    -   (c) an oxidant (optionally wherein the oxidant is         (2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)); and optionally

    -   (d) a salt (optionally wherein the salt is a sodium salt such as         a sodium phosphate salt such as disodium phosphate).

EXAMPLES

The followings Examples are illustrative only and should not be interpreted to limit the scope of the claimed subject matter.

Example 1

Title—Enantioselective Cross Dehydrogenative Coupling Reactions

Technical Field

The technical field of the disclosed subject matter relates to enantioselective cross dehydrogenative coupling (CDC) reactions and the use of the enantioselective CDC reactions for preparing compounds such as tetrahydropyrans and derivatives thereof.

Abstract

The inventors have developed an enantioselective cross-dehydrogenative coupling (CDC) reaction which may be utilized to prepare tetrahydropyrans and derivatives thereof. The disclosed CDC reaction combines in situ Lewis acid activation of a nucleophile together with the oxidative formation of a transient oxocarbenium electrophile, which leads to a productive and highly enantioselective CDC reaction. The disclosed CDC reaction represents one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. The disclosed CDC reactions may be utilized to access valuable tetrahydropyran motifs found in many natural products and bioactive small molecules.

Applications

The applications of the disclosed technology include, but are not limited to: (i) access to tetrahydropyran motifs found in many natural product and bioactive small molecules; and (ii) expansion of synthetic technology into different catalytic manifolds, for example, by using similar chemical set-ups as disclosed herein of different chemical structural classes to provided different product scaffolds.

Advantages

The advantages of the disclosed technology include, but are not limited to: (i) the disclosed technology allows for the use of unfunctionalized starting materials to access the core structural motif focused on in this work (i.e. pyrans); (ii) the disclosed technology is easy to implement into a standard chemical workflow (i.e., no specialized equipment is necessary for others to practice the disclosed technology); and (iii) the disclosed technology can be used to prepare diverse chemical products in ways that have not been previously reported or extensively explored.

Brief Summary of the Technology

The technology relates to enantioselective cross-dehydrogenative coupling (CDC) reactions that utilize in situ Lewis Acid activation in combination with oxidative formation of an oxocarbenium ion to provide a highly efficient and selective coupling reaction. The technology further is disclosed in Example 2 below and in Lee et al., “An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans,” J. Am. Chem. Soc. 2018, 140, 6212-6216; the content of which is incorporated herein by reference in its entirety.

Technical Description

Using catalytic amounts of a chiral Cu(II)-Box complex in combination with an organic oxidant (2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)), which was added dropwise via a syringe pump, we have demonstrated the enantioselective construction of pyranones from unfunctionalized ethers. The disclosed reaction is straightforward and simple to setup, where all of the necessary equipment should be found in a standard organic chemistry laboratory.

Others have tried using other catalyst manifolds to afford construction of similar chemical compounds. However, previous attempts have suffered from a lack of efficiency and only a small collection of chemical compounds that are compatible with the catalyst manifold.

Prior to the disclosure of this work, there were no concise and efficient methods to access pyrans from unfunctionalized starting materials. Pyrans are a common structural motif found in medicinally relevant natural products. With the disclosure of this work, the inventors have provided state-of-the-art technology to access these compounds.

Example 2

Reference is made to Lee et al., “An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans,” J. Am. Chem. Soc. 2018, 140, 6212-6216, the content of which is incorporated herein by reference in its entirety.

Title—An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans

Abstract

An enantioselective cross-dehydrogenative coupling (CDC) reaction to access tetrahydropyrans has been developed. This process combines in situ Lewis acid activation of a nucleophile in concert with the oxidative formation of a transient oxocarbenium electrophile, leading to a productive and highly enantioselective CDC. These advances represent one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. This system provides efficient access to valuable THP motifs found in many natural products and bioactive small molecules.

Introduction

Tetrahydropyrans (THPs) are key structural elements in numerous bioactive natural products and medicinally relevant compounds.¹ Due to the prevalence of THPs, multiple stereoselective processes have been developed for their construction, including Prins cyclizations,² hetero-Diels-Alder reactions,³ and intramolecular nucleophilic conjugate additions.⁴ Established methods to construct THPs in an enantioselective fashion typically focus on conjugate additions⁵ or activation by enamine/iminium intermediates,⁶ two approaches that are deployed extensively in total synthesis. Inspired by natural product targets of interest in our laboratory, as well as small molecules possessing intriguing biological activity, we envisioned a complementary and direct method for the enantioselective synthesis of substituted tetrahydropyran-4-ones. We have disclosed the use of β-hydroxy dioxinones as nucleophiles with aldehydes and isatins to undergo mild and stereoselective cyclizations in the presence of catalytic Lewis or Brønsted acids to access enantioenriched THPs.⁷ Our efforts in this area have enabled total syntheses of various natural products including exiguolide,⁸ neopeltolide,⁹ okilactomycin,¹⁰ and other naturally occurring compounds containing THPs.¹¹ Conceptually, moving beyond preformed nucleophiles such as dioxinones to simple β-ketoester systems presents opportunities for enantiocontrol, most likely through two-point/chelate binding, but also requires different activation modes to operate simultaneously in a single reaction flask.

Cross-dehydrogenative coupling (CDC) reactions have emerged as powerful approaches to forge C—C bonds from inert C—H bonds.¹² As a subset of C—H functionalization processes,¹³ CDC reactions are attractive because they do not require prefunctionalized starting materials, relying instead on oxidative activation followed by net loss of H₂ to facilitate C—C bond formation. Specifically, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) a strong oxidizing agent, promotes the formation of stabilized carbocations by benzylic and allylic C—H bond activation, and subsequent C—C bond formation.¹⁴ Mechanistically, DDQ mediated CDC reactions proceed via single electron transfer to form stabilized radical cations, followed by hydrogen atom abstraction to form the electrophilic coupling partner (e.g., oxocarbenium ion, iminium ion). Floreancig has effectively demonstrated that DDQ activation can facilitate racemic access to carbocycles and heterocycles via the oxidation of allylic ethers.¹⁵ Although enantioselective CDC reactions have been reported during the last decade,¹⁶ there is a dearth of highly enantioselective CDC reactions using oxocarbenium ion electrophiles in contrast to a plethora of enantioselective CDC reactions using iminium electrophiles (Scheme 1b).¹⁷ A major challenge to this approach is successfully integrating strongly oxidative conditions for oxocarbenium ion formation (e.g., DDQ) with stereodefining catalysts necessary for nucleophile activation (e.g., chiral Lewis acids) to a) promote a productive reaction, and b) induce stereocontrol around a transient, highly reactive oxocarbenium ion. Here, we report an enantioselective CDC of β-ketoesters with oxocarbenium ions to access substituted tetrahydropyrans with high yields and enantioselectivity through a merged chiral Lewis acid/oxidation strategy (Scheme 1c).

Scheme 1. CDC Processes and Reaction Design

(See FIG. 5 )

Results and Discussion

We initiated our investigations of this chiral Lewis acid/oxidant process using β-ketoester substrate 1a and found that Cu(II)-bisoxazoline (BOX) complex L1.Cu(OTf)₂ gave the desired product 2a as the sole diastereomer in 72% yield and 92:8 er at −70° C. (Scheme 2). Additional screening with chiral BOX ligands L2-L5 identified ligand L3 as optimal, furnishing 2a in 83% yield and 95:5 er upon further reaction dilution to 0.02 M.

After optimization the basic asymmetric CDC reaction with β-ketoester 1a, the general scope was explored (Table 1). When the aromatic ring on the cinnamyl ether was substituted with electron-donating groups at its para, meta, or ortho position, the reactions provided desirable tetrahydropyran-4-ones 2c-2g in high yields and stereoselectivity with exception of 2b. We observed that substrate 1b possessing a p-methoxycinnamyl group produced side products due to over-oxidation. Furthermore, reaction of 1b without a Cu(II) catalyst produced rac-2b in 70% yield in only 1 hour, suggesting the competitive background reaction of this highly reactive substrate also contributed to the observed reduction in stereoselectivity.

TABLE 1 Substrate Scope of β-Keto Esters 1^(a)

^(a)See Materials and Methods below for reaction details. Er determined by chiral-phase SFC analysis. Products 2 were obtained with >20:1 dr (trans/cis). ^(b)Performed at −30° C.

We then evaluated substrates substituted with electron-withdrawing groups at para, meta, and ortho positions. The reactions of 1h-1k provided desired products 2h-2k in moderate yields and high stereoselectivity. The results showed that high yields and stereoselectivity were observed for 1l and 1m containing naphthyl groups. The reaction of 1n containing a trisubstituted cinnamyl alkene afforded 2n in 87% yield and 97:3 er, while heteroaryl and conjugated ethers 1o-1q gave tetrahydropyran-4-ones 2o-2q in somewhat decreased yields and stereoselectivities. A survey of benzyl ethers revealed that only 4-methoxy-substituted substrates 1r-1t were capable of producing desired products 2r-2t with high stereoselectivity and moderate yield. Under the current conditions, we have not observed productive reactions using propargylic, unsubstituted allylic or ether substrates leading to tetrahydrofurans (i.e., 5 atom tether length). Instead, over-oxidation or no oxidation is observed (see Supp. Info.). However, with this successful proof of concept, investigations with various oxidation methods and Lewis acids to engage an even larger range of substrate classes are ongoing.

Attempts to access enantioenriched tetrahydropyran-4-ones without the β-ketoester were unsuccessful, as enol acetate 3 provided racemic 4 in 68% yield (Scheme 3a). This observation supports the hypothesis that the β-ketoester is crucial for stereoselectivity by coordination with the Cu(II)/BOX catalyst. In an attempt to probe whether an enantioselective intermolecular CDC reaction was possible, cinnamyl methyl ether was exposed to methyl acetoacetate in the presence of L3.Cu(OTf)₂ to afford 5 (Scheme 3b). Although the intermediate oxocarbenium ion could potentially undergo both 1,2- and 1,4-addition, the 1,2-addition adduct 5 was observed (as detected by NMR spectroscopy). Unfortunately, attempts to isolate 5 have been unsuccessful, due to facile elimination of the □-methoxy group to form enone 6 (2.7:1 E/Z mixture).

The stereochemical model of the reaction with 1a, Cu(II)/BOX and DDQ is based on a reported X-ray crystal structure of [L1.Cu(H₂O)₂](SbF₆)₂ by replacement of H₂O ligands with the oxocarbenium ion of 1a (FIG. 1 ).¹⁹ With the oxidized substrate bound to the Cu(II) center via bidentate chelation, the bulky tert-butyl group of the L3.Cu(II) complex shields the top face of the bound substrate (Si face) which in turn places the transient oxocarbenium ion below. During the reaction, the metal-bound enol(ate) adds to the Re face of the oxocarbenium ion via a pseudo chair-like conformation to provide product 2a with S configuration at the C1′ position, consistent with observed stereochemistry. This model also supports the observed relative C1′-C2′ trans relationship of the products.

A practical advantage of this strategy is the ease of synthetically elaborating these β-keto esters (Scheme 4). Conventional heating in DMF/H₂O provided the decarboxylated product 4 in 77% yield, where methylation of 2a gave 3,3-disubstituted tetrahydropyran-4-one 7 in excellent yield with 13:1 dr. Exposure of β-ketoesters 2a or 7 to L-selectride provided the corresponding tetrahydropyran-4-ol 8 or 9, while LiAlH₄ reduction of 7 furnished diol 10.²⁰ Functionalization of the 6-position of the 7 has also been demonstrated. First, cyclic enone 11 was prepared via dehydrogenation using 1 atm of O₂ in the presence of Pd(TFA)₂ in DMSO.²¹ Rh(I)-catalyzed 1,4-addition of phenylboronic acid produced 12,²² and conjugate addition of an alkyl cuprate provided 13 as the trans diastereomers in both reactions.^(20,23) Lastly, Mukaiyama-Michael addition proceeded to afford 14 with 10:1 diasteromeric ratio.^(23,24) Notably, while many synthetic methods exist for cis-2,6-tetrahydropyran structures,²⁵ there are far fewer preparations for trans-2,6-tetrahydropyrans.²⁶

To substitute DDQ as a reagent, we investigated complementary oxidation processes to form the oxocarbenium ion. A recent report of photoredox catalysis being used to generate oxocarbenium ions²⁷ inspired us to leverage this approach and trap the oxocarbenium ion with our tethered carbon nucleophile. Gratifyingly, the use of Sc(OTf)₃, Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, blue LEDs, and bromochloroform provided access to rac-2a in 90% yield (Scheme 5). To date, these photoredox conditions are not yet compatible with various chiral ligands to induce enantioselectivity.²⁸

In summary, a chiral Lewis acid-catalyzed intramolecular cross-dehydrogenative coupling of β-ketoesters has been developed. This oxidative process utilizes unfunctionalized starting materials to provide chiral 2-substituted tetrahydropyrans with excellent yields and stereoselectivity. The in situ generation of both nucleophilic and electrophilic partners specifically provides new opportunities for enantioselective oxocarbenium ion-driven reactions and CDC processes in general. Investigations in our laboratory towards leveraging this chiral Lewis acid/oxidation system with new substrate classes as well as the use of visible light mediated oxidation in asymmetric transformations are currently underway.

Materials and Methods

1. General Information

All reactions were carried out under a nitrogen atmosphere in oven-dried glassware with magnetic stirring. All organic solvents were purified by passage through a bed of activated alumina. (See Pangborn, A. B.; Giardelo, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518). Purification of reaction products was carried out by flash chromatography using EM Reagent or Silicycle silica gel 60 (230-400 mesh). Analytical thin layer chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization was accomplished with UV light and ceric ammonium nitrate stain, potassium permanganate stain or ninhydrin stain followed by heating. 1H NMR spectroscopy spectra were recorded on a Bruker Avance III 400 or 500 MHz w/direct cryoprobe (400 or 500 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCl₃ at 7.26 ppm). Data are reported as (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad; coupling constant(s) in Hz, integration). Proton-decoupled 13C NMR spectroscopy spectra were recorded on a Bruker Avance 500 MHz w/ direct cryoprobe (125 MHz) spectrometer and are reported in ppm using solvent as an internal standard (CDCl₃ at 77.16 ppm). SFC analysis was performed on an Agilent 1290 Infinity, using Chiralpak IA-3, IB-3, IC-3, ID-3, and IG-3 columns. Mass spectra data were obtained on a Varian 1200 Quadrupole Mass Spectrometer and Micromass Quadro II Spectrometer or a WATERS Acquity-H UPLC-MS with a signal quad detector (ESI). L.Cu(OTf)₂ complexes were prepared according to literature procedures. (See Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541). Stereochemical models were optimized using the Spartan 08 program implement of semi-empirical PM3 calculation. (See Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209).

2. General Procedure for Synthesis of β-Keto Esters (1

Acrylonitrile (0.39 mL, 6.0 mmol) was added to a mixture of the corresponding cinnamyl alcohol (5.0 mmol) and 50 μL of aqueous NaOH (40%) at room temperature (If the corresponding cinnamyl alcohol was solid, 2 mL of benzene or THF was added). The reaction mixture was stirred for 15 h at same temperature, then neutralized with aqueous HCl (1 N), and diluted with ethyl acetate. The organic layer was washed with 5% aqueous NaOH followed by brine, evaporated in vacuo, and dried thoroughly to afford the desired compound. The crude compound was used for the next steps without purification. (See Krishna, T. R.; Jayaraman, N, J. Org. Chem. 2003, 68, 9694).

To an oven dried 100 mL 3 neck round bottom flask equipped with a reflux condenser under N₂ was added a magnetic stir bar, Zinc (1.63 g, 25 mmol), and 15 mL of THF. The solution was heated to reflux, and then 0.25 mL of methyl bromoacetate was added slowly to activate the zinc (gray color to hunter green). Once the zinc was activated, the corresponding nitrile was added, followed by slow addition of 1.87 mL of methyl bromoacetate (20 mmol) over 1 h. The reaction stirred for 2 h, and was then removed from heat. The saturated NaHCO₃ solution was added to quench the reaction, followed by addition of diethyl ether. The heterogeneous solution was filtered over a pad of Celite with diethyl ether. The aqueous layer was extracted with diethyl ether, dried and concentrated in vacuo. The 2.86 mL of AcOH (50 mmol), 10 mL of THF, and 10 mL of H₂O were added to the crude compound. The reaction stirred for 1 h at ambient temperature, and then saturated NaHCO₃ solution was added to quench the reaction. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexanes:EtOAc=4:1) to give the corresponding β-keto esters 1. (The β-keto esters 1 were isolated with the corresponding enol tautomer in 11:1 ratio.)

Yellow oil. (931.2 mg, 71% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.07 (s, 0.1H, enol), 7.41-7.35 (m, 2H, keto+enol), 7.34-7.28 (m, 2H, keto+enol), 7.26-7.21 (m, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.25 (dt, J=15.9, 6.1 Hz, 1H, keto+enol), 5.10 (s, 0.1H, enol), 4.13 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.75 (t, J=6.2 Hz, 2H, keto+enol), 3.73 (s, 3H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.0, 167.6, 136.7, 136.7, 132.7, 132.6, 128.6, 127.2, 126.6, 126.5, 125.9, 125.7, 90.2, 71.8, 71.7, 66.4, 64.9, 52.4, 51.2, 49.6, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₈O₄ [M+Na]⁺: 285.110. Found: 285.109.

Yellow oil. (1.08 g, 78% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.15 (s, 0.1H, enol), 7.38 (d, J=7.5 Hz, 2H, keto+enol), 7.31 (t, J=7.6 Hz, 2H, keto+enol), 7.24 (t, J=7.3 Hz, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.26 (dt, J=15.9, 6.1 Hz, 1H, keto+enol), 5.08 (s, 0.1H, enol), 4.19 (q, J=7.2 Hz, 2H, keto+enol), 4.14 (dd, J=6.1, 1.4 Hz, 2H, keto+enol), 3.76 (t, J=6.2 Hz, 1.8H, keto), 3.72 (t, J=6.4 Hz, 0.2H, enol), 3.50 (s, 1.8H, keto), 2.84 (t, J=6.2 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol), 1.27 (t, J=7.1 Hz, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.5, 175.6, 172.7, 167.2, 136.7, 132.8, 132.7, 128.7, 127.9, 127.8, 126.6, 125.9, 125.8, 90.5, 71.9, 71.7, 66.5, 65.0, 61.5, 60.2, 49.9, 43.2, 35.8, 14.4, 14.2.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1260.

Colorless oil. (1.02 g, 67% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.29 (s, 0.1H, enol), 7.38 (d, J=7.5 Hz, 2H, keto+enol), 7.31 (t, J=7.6 Hz, 2H, keto+enol), 7.24 (t, J=7.3 Hz, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.26 (dt, J=15.9, 6.1 Hz, 1H, keto+enol), 4.98 (s, 0.1H, enol), 4.14 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.76 (t, J=6.3 Hz, 1.8H, keto), 3.71 (t, J=6.6 Hz, 0.2H, enol), 3.41 (s, 1.8H, keto), 2.83 (t, J=6.3 Hz, 1.8H, keto), 2.49 (t, J=6.6 Hz, 0.2H, enol), 1.49 (s, 0.9H, enol), 1.47 (s, 8.1H, keto).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.9, 174.9, 172.7, 166.4, 136.7, 132.7, 132.6, 128.7, 127.8, 126.6, 126.0, 125.9, 91.9, 82.1, 81.0, 71.9, 71.7, 66.5, 65.0, 51.2, 43.1, 35.8, 28.4, 28.1.

HRMS (ESI) calculated for C₁₈H₂₄O₄[M+Na]⁺: 327.1572. Found: 327.1577.

Colorless oil. (879.8 mg, 52% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.40-7.29 (m, 8H, keto+enol), 7.27-7.22 (m, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.24 (dt, J=15.9, 6.1 Hz, 1H, keto+enol), 5.18 (s, 2H, keto+enol), 5.12 (s, 0.1H, enol), 4.16 (dd, J=6.0, 1.5 Hz, 0.2H, enol), 4.12 (dd, J=6.1, 1.5 Hz, 1.8H, keto), 3.75 (t, J=6.2 Hz, 1.8H, keto), 3.73-3.70 (m, 0.2H, enol), 3.57 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 176.2, 172.5, 167.0, 136.7, 135.4, 132.8, 132.7, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 127.9, 126.7, 125.8, 90.4, 71.9, 71.8, 67.3, 66.4, 65.9, 65.0, 49.9, 43.3, 35.9.

HRMS (ESI) calculated for C₂₁H₂₂O₄[M+Na]⁺: 361.1416. Found: 361.1418.

Orange oil. (185.0 mg, 12% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm 16.13 (s, 1H), 7.88 (d, J=6.9 Hz, 2H), 7.52 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.7 Hz, 2H), 7.37 (d, J=7.5 Hz, 2H), 7.30 (t, J=7.6 Hz, 2H), 7.24 (t, J=7.3 Hz, 1H), 6.62 (d, J=15.9 Hz, 1H), 6.33-6.24 (m, 2H), 4.19 (dd, J=6.0, 1.4 Hz, 2H), 3.84 (t, J=6.3 Hz, 2H), 2.75 (t, J=6.4 Hz, 2H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 194.6, 183.3, 136.8, 134.9, 132.8, 132.5, 128.8, 128.7, 127.9, 127.2, 126.7, 125.9, 97.0, 71.9, 66.2, 40.0.

HRMS (ESI) calculated for C₂₀H₂₀O₃[M+Na]⁺: 331.1310. Found: 331.1311.

Colorless oil. (1.04 g, 71% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 7.31 (d, J=8.7 Hz, 2H, keto+enol), 6.85 (d, J=8.7 Hz, 2H, keto+enol), 6.53 (d, J=15.9 Hz, 1H, keto+enol), 6.11 (dt, J=15.9, 6.3 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.11 (dd, J=6.2, 1.4 Hz, 2H, keto+enol), 3.80 (s, 3H, keto+enol), 3.77-3.67 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H, keto), 2.51 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6, 159.5, 132.6, 132.5, 129.4, 127.8, 123.6, 123.4, 114.1, 90.2, 72.1, 71.9, 66.3, 64.8, 55.4, 52.5, 51.3, 49.6, 43.3, 35.8.

HRMS (ESI) calculated for C16H₂₀O₅ [M+Na]⁺: 315.121. Found: 315.122.

Yellow oil. (1.13 g, 77% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.23 (t, J=7.9 Hz, 1H, keto+enol), 6.98 (d, J=7.6 Hz, 1H, keto+enol), 6.92 (s, 1H, keto+enol), 6.80 (dd, J=8.2, 1.9 Hz, 1H, keto+enol), 6.56 (d, J=15.9 Hz, 1H, keto+enol), 6.25 (dt, J=15.9, 6.1 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.14 (dd, J=6.0, 1.5 Hz, 2H, keto+enol), 3.81 (s, 3H, keto+enol), 3.79-3.72 (m, 5H, keto+enol), 3.53 (s, 1.8H, keto), 2.83 (t, J=6.1 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.37, 167.63, 159.94, 139.67, 138.19, 132.67, 129.78, 129.68, 129.59, 126.29, 126.14, 120.03, 119.34, 118.03, 113.59, 113.54, 113.10, 111.90, 111.26, 90.26, 71.86, 70.39, 66.49, 65.01, 55.36, 52.51, 52.07, 49.69, 43.28, 35.85.

HRMS (ESI) calculated for C₁₆H₂₀O₅ [M+Na]⁺: 315.121. Found: 315.122.

Colorless oil. (1.02 g, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 7.43 (dd, J=7.6, 1.8 Hz, 1H, keto+enol), 7.25-7.20 (m, 1H, keto+enol), 6.97-6.82 (m, 3H, keto+enol), 6.27 (dt, J=16.1, 6.2 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.14 (dd, J=6.2, 1.5 Hz, 1.8H, keto+enol), 3.84 (s, 3H, keto+enol), 3.79-3.69 (m, 5H, keto+enol), 3.53 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.5, 175.9, 173.1, 167.7, 156.9, 129.4, 128.9, 128.9, 127.9, 127.8, 127.1, 127.1, 126.5, 126.4, 126.3, 125.8, 125.7, 120.8, 120.7, 110.9, 90.2, 72.4, 72.3, 66.3, 64.9, 64.4, 55.5, 52.5, 51.3, 49.6, 43.3, 35.8.

HRMS (ESI) calculated for C₁₆H₂₀O₅ [M+Na]⁺: 315.1208. Found: 315.1213.

Pale yellow oil. (994.8 mg, 72% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.28 (d, J=8.0 Hz, 2H, keto+enol), 7.12 (d, J=7.9 Hz, 2H, keto+enol), 6.56 (d, J=15.9 Hz, 1H, keto+enol), 6.20 (dt, J=15.9, 6.2 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.12 (dd, J=6.2, 1.5 Hz, 2H, keto+enol), 3.82-3.68 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 2H, keto), 2.51 (t, J=6.5 Hz, 0.2H, enol), 2.33 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6, 137.7, 137.7, 133.9, 132.8, 132.7, 129.4, 126.5, 124.8, 124.7, 90.2, 72.0, 71.9, 66.4, 64.9, 52.5, 51.3, 49.7, 43.3, 35.8, 21.3.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1269.

Pale yellow oil. (953.3 mg, 69% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.24-7.16 (m, 3H, keto+enol), 7.10-7.04 (m, 1H, keto+enol), 6.56 (d, J=15.9 Hz, 1H, keto+enol), 6.24 (dt, J=15.9, 6.1 Hz, 1H, keto+enol), 5.10 (s, 0.1H, enol), 4.13 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.82-3.66 (m, 5H, keto+enol), 3.53 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol), 2.34 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6, 138.2, 136.6, 132.9, 132.8, 131.3, 128.7, 128.6, 128.6, 128.5, 127.4, 127.3, 125.7, 125.6, 123.8, 123.7, 90.2, 71.9, 64.9, 52.5, 49.7, 43.3, 21.5.

HRMS (ESI) calculated for C₁₆H₂₀O₄[M+Na]⁺: 299.1259. Found: 299.1263.

Yellow oil. (994.6 mg, 72% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.07 (s, 0.1H, enol), 7.47-7.41 (m, 1H, keto+enol), 7.19-7.11 (m, 3H, keto+enol), 6.81 (d, J=15.8 Hz, 1H, keto+enol), 6.14 (dt, J=15.8, 6.1 Hz, 1H, keto+enol), 5.10 (s, 0.1H, enol), 4.16 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.77 (t, J=6.2 Hz, 2H, keto+enol), 3.73 (s, 3H, keto+enol), 3.53 (s, 1.8H, keto), 2.84 (t, J=6.2 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz, 0.2H, enol), 2.35 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6, 135.8, 135.6, 130.6, 130.5, 130.4, 127.8, 127.7, 127.2, 127.1, 126.2, 125.9, 90.2, 72.1, 71.9, 66.4, 64.9, 52.5, 51.3, 49.7, 43.3, 35.9, 19.9.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1265.

Colorless oil. (1.25 g, 73% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.43 (d, J=8.5 Hz, 2H, keto+enol), 7.24 (d, J=8.4 Hz, 2H, keto+enol), 6.52 (d, J=16.0 Hz, 1H, keto+enol), 6.24 (dt, J=16.0, 5.9 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.11 (dd, J=6.0, 1.5 Hz, 2H, keto+enol), 3.79-3.67 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.1 Hz, 1.8H, keto), 2.51 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.0, 167.6, 135.7, 131.8, 131.4, 131.3, 128.1, 126.8, 126.7, 121.6, 90.3, 71.7, 71.5, 66.6, 65.1, 52.5, 51.3, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇BrO₄[M+Na]⁺: 363.0208. Found: 363.0213.

Yellow oil. (1.28 g, 75% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.52 (s, 1H, keto+enol), 7.36 (d, J=7.9 Hz, 1H, keto+enol), 7.28 (d, J=7.7 Hz, 1H, keto+enol), 7.17 (t, J=7.8 Hz, 1H, keto+enol), 6.52 (d, J=15.9 Hz, 1H, keto+enol), 6.25 (dt, J=15.9, 5.9 Hz, 1H, keto+enol), 5.09 (s, OH, enol), 4.13 (dd, J=5.8, 1.6 Hz, 2H, keto+enol), 3.81-3.67 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.51 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.0, 167.6, 138.9, 131.0, 1309, 130.7, 130.6, 130.3, 130.2, 129.5, 127.5, 125.2, 122.9, 90.3, 71.5, 71.4, 65.1, 64.9, 52.5, 52.0, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇BrO₄[M+Na]⁺: 363.0208. Found: 363.0204.

Yellow oil. (1.13 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.36 (s, 1H, keto+enol), 7.25-7.17 (m, 3H, keto+enol), 6.53 (d, J=15.9 Hz, 1H, keto+enol), 6.26 (dt, J=15.9, 5.9 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.13 (dd, J=5.8, 1.5 Hz, 2H, keto+enol), 3.80-3.68 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.51 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.1, 167.6, 138.6, 134.6, 131.1, 131.0, 129.9, 129.8, 128.0, 127.8, 127.7, 127.6, 127.4, 126.6, 124.8, 90.3, 71.6, 71.4, 65.3, 65.1, 52.5, 51.3, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇ClO₄ [M+Na]⁺: 319.0713. Found: 319.0714.

Pale yellow oil. (1.04 g, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.53 (dd, J=7.6, 1.8 Hz, 1H, keto+enol), 7.34 (dd, J=7.7, 1.6 Hz, 1H, keto+enol), 7.22 (td, J=7.5, 1.6 Hz, 1H, keto+enol), 7.18 (td, J=7.6, 1.8 Hz, 1H, keto+enol), 6.98 (d, J=15.9 Hz, 1H, keto+enol), 6.24 (dt, J=16.0, 5.9 Hz, 1H, keto+enol), 5.10 (s, 0.1H, enol), 4.17 (dd, J=6.0, 1.6 Hz, 2H, keto+enol), 3.78 (t, J=6.1 Hz, 2H, keto+enol), 3.73 (s, 3H, keto+enol), 3.53 (s, 1.8H, keto), 2.84 (t, J=6.1 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.7, 173.1, 167.6, 134.9, 133.2, 131.6, 129.8, 128.9, 128.8, 128.7, 128.7, 127.2, 127.1, 127.1, 127.0, 90.3, 71.8, 71.6, 66.6, 65.1, 63.8, 52.5, 51.3, 49.7, 43.3, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇ClO₄ [M+Na]⁺: 319.0713. Found: 319.0710.

Colorless oil. (1.11 g, 71% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.09 (s, 0.1H, enol), 7.86-7.76 (m, 3H, keto+enol), 7.74 (s, 1H, keto+enol), 7.60 (dd, J=8.5, 1.8 Hz, 1H, keto+enol), 7.52-7.40 (m, 2H, keto+enol), 6.76 (d, J=15.9 Hz, 1H, keto+enol), 6.39 (dt, J=16.0, 6.1 Hz, 1H, keto+enol), 5.12 (s, 0.1H, enol), 4.20 (dd, J=6.0, 1.5 Hz, 2H, keto+enol), 3.80 (t, J=6.2 Hz, 2H, keto+enol), 3.74 (s, 3H, keto+enol), 3.54 (s, 1.8H, keto), 2.85 (t, J=6.2 Hz, 1.8H, keto), 2.55 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6, 134.2, 133.7, 133.2, 132.8, 132.8, 128.3, 128.1, 128.0, 127.8, 127.8, 126.7, 126.4, 126.3, 126.2, 126.1, 126.0, 123.7, 90.3, 72.0, 71.8, 65.1, 65.0, 52.5, 51.3, 49.7, 43.3, 35.9.

HRMS (ESI) calculated for C₁₉H₂₀O₄ [M+Na]⁺: 335.1259. Found: 335.1258.

Yellow oil. (1.08 g, 69% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.11 (s, 0.1H, enol), 8.18-8.03 (m, 1H, keto+enol), 7.89-7.82 (m, 1H, keto+enol), 7.79 (d, J=8.2 Hz, 1H, keto+enol), 7.61 (d, J=7.1 Hz, 1H, keto+enol), 7.55-7.47 (m, 2H, keto+enol), 7.47-7.43 (m, 1H, keto+enol), 7.36 (d, J=15.7 Hz, 1H, keto+enol), 6.30 (dt, J=15.7, 5.9 Hz, 1H, keto+enol), 5.14 (s, 0.1H, enol), 4.26 (dd, J=5.9, 1.6 Hz, 2H, keto+enol), 3.84 (t, J=6.2 Hz, 1.8H, keto), 3.80 (t, J=6.4 Hz, 0.2H, enol), 3.74 (s, 3H, keto+enol), 3.55 (s, 1.8H, keto), 2.87 (t, J=6.1 Hz, 1.8H, keto), 2.57 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.4, 175.8, 173.1, 167.6, 134.5, 133.7, 131.3, 129.8, 129.6, 129.2, 129.1, 128.6, 128.2, 128.2, 126.2, 125.9, 125.7, 124.1, 124.1, 123.9, 90.3, 72.0, 71.9, 66.5, 65.1, 52.5, 51.3, 49.7, 43.3, 35.9.

HRMS (ESI) calculated for C₁₉H₂₀O₄ [M+Na]⁺: 335.1259. Found: 335.1257.

Yellow oil. (967.2 mg, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.04 (s, 0.1H, enol), 7.30 (t, J=7.5 Hz, 2H, keto+enol), 7.27-7.23 (m, 2H, keto+enol), 7.19 (t, J=7.2 Hz, 1H, keto+enol), 6.45 (s, 1H, keto+enol), 5.08 (s, 0.1H, enol), 4.01 (s, 0.2H, enol), 3.99 (s, 1.8H, keto), 3.75-3.63 (m, 5H, keto+enol), 3.51 (s, 1.8H, keto), 2.81 (t, J=6.1 Hz, 1.8H, keto), 2.50 (t, J=6.4 Hz, 0.2H, enol), 1.84 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.9, 173.0, 167.6, 137.5, 137.5, 135.1, 135.0, 129.0, 129.0, 128.2, 127.2, 127.1, 126.6, 126.6, 90.2, 77.4, 77.2, 66.1, 64.8, 52.4, 51.2, 49.7, 43.2, 35.8, 15.5.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1254.

Yellow oil. (1.68 g, 74% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.08 (s, 0.1H, enol), 7.98 (d, J=8.3 Hz, 1H, keto+enol), 7.75 (d, J=8.4 Hz, 2H, keto+enol), 7.72 (d, J=7.9 Hz, 1H, keto+enol), 7.59 (s, 1H, keto+enol), 7.36-7.30 (m, 1H, keto+enol), 7.29-7.24 (m, 1H, keto+enol), 7.20 (d, J=8.2 Hz, 2H, keto+enol), 6.66 (d, J=16.2 Hz, 1H, keto+enol), 6.32 (dt, J=16.1, 6.0 Hz, 1H, keto+enol), 5.11 (s, 0.1H, enol), 4.15 (dd, J=6.1, 1.5 Hz, 1H, keto+enol), 3.77 (t, J=6.2 Hz, 1H, keto+enol), 3.73 (s, 3H, keto+enol), 3.53 (s, 1.8H, keto), 2.84 (t, J=6.1 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz, 0.2H, enol), 2.32 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.1, 167.6, 145.2, 135.6, 135.2, 130.0, 129.1, 127.2, 127.0, 127.0, 125.1, 124.3, 124.3, 123.6, 123.4, 123.2, 120.5, 120.1, 113.9, 90.3, 72.1, 71.9, 66.5, 65.0, 52.5, 51.3, 49.7, 43.2, 35.8, 21.7.

HRMS (ESI) calculated for C₂₄H₂₅NO₆S [M+Na]⁺: 478.1300. Found: 478.1308.

Yellow oil. (1.01 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 7.18-7.14 (m, 1H, keto+enol), 6.98-6.93 (m, 2H, keto+enol), 6.71 (d, J=15.7 Hz, 1H, keto+enol), 6.08 (dt, J=15.7, 6.1 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.09 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.79-3.71 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H, keto), 2.51 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.1, 167.6, 141.8, 127.5, 126.0, 126.0, 125.9, 125.8, 125.5, 125.4, 124.6, 124.6, 90.2, 71.5, 71.4, 66.5, 65.0, 52.5, 51.3, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₃H₁₆O₄S [M+Na]⁺: 291.0667. Found: 291.0662.

Yellow oil. (1.10 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.39 (d, J=7.4 Hz, 2H, keto+enol), 7.31 (t, J=7.6 Hz, 2H, keto+enol), 7.22 (t, J=7.3 Hz, 1H, keto+enol), 6.77 (dd, J=15.6, 10.5 Hz, 1H, keto+enol), 6.55 (d, J=15.7 Hz, 1H, keto+enol), 6.40 (dd, J=15.0, 10.7 Hz, 1H, keto+enol), 5.85 (dt, J=15.2, 6.2 Hz, 1H, keto+enol), 5.09 (s, 0.1H, enol), 4.06 (dd, J=6.3, 1.4 Hz, 2H, keto+enol), 3.78-3.67 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H, keto), 2.51 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6, 137.2, 133.2, 133.2, 133.0, 133.0, 129.9, 129.7, 128.7, 128.3, 128.2, 127.8, 126.5, 90.2, 71.6, 71.4, 65.3, 65.0, 52.5, 51.3, 49.7, 43.3, 35.8, 15.2.

HRMS (ESI) calculated for C₁₇H₂₀O₄ [M+Na]⁺: 311.1259. Found: 311.1256.

Pale yellow oil. (998.6 mg, 75% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.03 (s, 0.1H, enol), 7.23 (d, J=8.6 Hz, 2H, keto+enol), 6.87 (d, J=8.7 Hz, 2H, keto+enol), 5.06 (s, 0.1H, enol), 4.45 (s, 0.2H, enol), 4.43 (s, 1.8H, keto), 3.79 (s, 3H, keto+enol), 3.74-3.69 (m, 5H, keto+enol), 3.49 (s, 1.8H, keto), 2.80 (t, J=6.2 Hz, 1.8H, keto), 2.49 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.9, 173.0, 167.6, 159.4, 130.1, 129.5, 129.4, 113.9, 90.1, 73.0, 72.8, 66.1, 64.8, 55.4, 52.4, 51.2, 49.6, 43.3, 35.8.

HRMS (ESI) calculated for C₁₄H₁₈O₅ [M+Na]⁺: 289.1052. Found: 289.1046.

Yellow oil. (1.13 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.04 (s, 0.1H, enol), 6.88-6.78 (m, 3H, keto+enol), 5.07 (s, 0.1H, enol), 4.45 (s, 0.2H, enol), 4.43 (s, 1.8H, keto), 3.88 (s, 3H, keto+enol), 3.86 (s, 3H, keto+enol), 3.74-3.64 (m, 5H, keto+enol), 3.49 (s, 1.8H, keto), 2.80 (t, J=6.1 Hz, 1.8H, keto), 2.49 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.9, 173.0, 167.6, 149.1, 148.8, 130.6, 120.4, 120.3, 111.1, 111.0, 111.0, 110.9, 90.1, 73.3, 73.1, 66.1, 64.8, 56.0, 55.9, 55.8, 52.4, 51.2, 49.6, 43.2, 35.7.

HRMS (ESI) calculated for C₁₅H₂₀O₆[M+Na]⁺: 319.1158. Found: 319.1154.

Yellow oil. (1.19 g, 73% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 6.53 (s, 2H, keto+enol), 5.08 (s, 0.1H, enol), 4.44 (s, 0.2H, enol), 4.42 (s, 1.8H, keto), 3.84 (s, 6H, keto+enol), 3.81 (s, 3H, keto+enol), 3.74 (t, J=6.1 Hz, 2H, keto+enol), 3.70 (s, 3H, keto+enol), 3.49 (s, 1.8H, keto), 2.82 (t, J=6.1 Hz, 1.8H, keto), 2.51 (t, J=6.3 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 175.8, 173.0, 167.5, 153.4, 137.5, 137.4, 133.8, 133.7, 90.2, 73.5, 73.3, 66.4, 65.0, 60.9, 56.1, 56.1, 52.4, 51.2, 49.6, 43.1, 35.7.

HRMS (ESI) calculated for C₁₆H₂₂O₇ [M+Na]⁺: 349.1263. Found: 349.1259.

Colorless oil. (967.0 mg, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.03 (s, 0.1H, enol), 7.39 (d, J=7.6 Hz, 2H, keto+enol), 7.32 (t, J=7.6 Hz, 2H, keto+enol), 7.24 (t, J=7.9 Hz, 1H, keto+enol), 6.52 (d, J=16.0 Hz, 1H, keto+enol), 6.08 (dd, J=16.0, 7.7 Hz, 1H, keto+enol), 5.08 (s, 0.1H, enol), 4.00 (p, J=6.6 Hz, 1H, keto+enol), 3.77 (dt, J=9.7, 6.2 Hz, 1H, keto+enol), 3.73 (s, 3H, keto+enol), 3.63 (dt, J=9.7, 6.3 Hz, 1H, keto+enol), 3.52 (s, 1.8H, keto), 2.84-2.73 (m, 1.8H, keto), 2.49 (t, J=6.6 Hz, 0.2H, enol), 1.31 (d, J=6.4 Hz, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.6, 176.0, 173.1, 167.7, 136.6, 131.6, 131.5, 131.4, 131.3, 128.7, 127.8, 126.6, 90.1, 77.2, 77.0, 64.6, 63.2, 52.4, 51.2, 49.7, 43.5, 36.0, 21.7.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1255.

Yellow oil. (885.0 mg, 68% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.47-7.42 (m, 2H, keto+enol), 7.34-7.28 (m, 3H, keto+enol), 5.11 (s, 0.1H, keto+enol), 4.38 (s, 0.2H, enol), 4.36 (s, 1.8H, keto), 3.86 (t, J=6.1 Hz, 1.8H, keto), 3.82 (t, J=6.4 Hz, 0.2H, enol), 3.72 (s, 3H, keto+enol), 3.53 (s, 1.8H, keto), 2.85 (t, J=6.2 Hz, 1.8H, keto), 2.54 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 175.5, 173.0, 167.6, 131.9, 131.8, 128.6, 128.6, 128.5, 128.4, 122.6, 122.6, 90.2, 86.6, 86.6, 84.9, 84.8, 66.1, 64.7, 59.3, 59.1, 52.5, 51.3, 49.5, 43.1, 35.5.

HRMS (ESI) calculated for C1411604 [M+Na]⁺: 283.0946. Found: 283.0943.

Pale yellow oil. (689.0 mg, 74% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.02 (s, 0.1H, enol), 5.91-5.80 (m, 1H, keto+enol), 5.24 (dd, J=17.2, 1.7 Hz, 1H, keto+enol), 5.16 (dd, J=10.4, 1.6 Hz, 1H, keto+enol), 5.05 (s, 0.1H, enol), 3.95 (dt, J=5.6, 1.5 Hz, 2H, keto+enol), 3.72 (s, 3H, keto+enol), 3.69 (t, J=6.2 Hz, 1.8H, keto), 3.64 (t, J=6.5 Hz, 0.2H, enol), 3.49 (s, 1.8H, keto), 2.79 (t, J=6.2 Hz, 1.8H, keto), 2.47 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.0, 167.6, 134.6, 134.5, 117.3, 117.3, 90.1, 72.2, 72.1, 66.4, 64.9, 52.4, 51.2, 49.6, 43.2, 35.8.

HRMS (ESI) calculated for C₉H₁₄O₄ [M+Na]⁺: 209.0790. Found: 209.0782.

Colorless oil. (567.4 mg, 56% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.02 (s, 0.1H, enol), 5.06 (s, 0.1H, enol), 3.73 (d, J=5.5 Hz, 3H, keto+enol), 3.67 (t, J=6.2 Hz, 1.8H, keto), 3.63 (t, J=6.6 Hz, 0.2H, enol), 3.50 (s, 1.8H, keto), 3.40 (t, J=6.6 Hz, 2H, keto+enol), 2.77 (t, J=6.2 Hz, 1.8H, keto), 2.47 (t, J=6.5 Hz, 0.2H, enol), 1.58-1.45 (m, 2H, keto+enol), 1.38-1.29 (m, 2H, keto+enol), 0.90 (t, J=7.4 Hz, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.7, 176.1, 173.1, 167.7, 90.0, 71.2, 71.0, 67.0, 65.6, 52.5, 52.4, 51.3, 50.0, 49.7, 43.3, 35.8, 31.8, 30.3, 19.4, 14.0.

HRMS (ESI) calculated for C₁₀H₁₈O₄[M+Na]⁺: 225.1103. Found: 225.1100.

To a suspension of 60% NaH (264 mg, 6.6 mmol) in THF (20 mL) at 0° C. was added cinnamyl alcohol (492.5 mg, 3.0 mmol), and the resulting mixture was stirred at ambient temperature for 2 h. To this mixture was then added ethyl 4-chloroacetateacetate (0.41 mL, 3.0 mmol) dropwise over 30 min, and the resulting clear yellow solution was stirred at ambient temperature overnight before it was cooled to 5° C., acidified to pH=4 using 5% HCl and extracted with the EtOAc (2×25 mL). The combined organics were washed with brine, dried over MgSO₄, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (hexanes:EtOAc=10:1 to 4:1) to give the corresponding β-keto esters 1x as colorless oil (605.9 mg, 77% yield).

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 11.99 (s, 0.1H, enol), 7.39 (d, J=7.3 Hz, 2H, keto+enol), 7.33 (t, J=7.5 Hz, 2H, keto+enol), 7.29-7.22 (m, 1H, keto+enol), 6.62 (d, J=15.9 Hz, 1H, keto+enol), 6.26 (dt, J=15.9, 6.2 Hz, 1H, keto+enol), 5.33 (s, 0.1H, enol), 4.23 (dd, J=6.2, 1.4 Hz, 2H, keto+enol), 4.21-4.16 (m, 4H, keto+enol), 3.54 (s, 1.8H, keto), 1.26 (t, J=7.1 Hz, 3H, keto+enol).

LRMS (ESI) calculated for C₉H₁₄O₄[M+H]⁺: 263.1. Found: 263.1.

To an oven dried 250 mL round bottom flask equipped with a magnetic stir bar was added the 1a (786.9 mg, 3.0 mmol), 144.0 mg of NaH (60% in oil, 3.6 mmol), and 40 mL of THF at 0° C. Methyl iodide (0.75 mL, 12.0 mmol) was added to the solution. The solution was stirred for 1 h at 0° C. and then stirred for 14 h at ambient temperature additionally. The saturated NH₄C1 solution was added to quench the reaction, followed by addition of ethyl acetate. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:3) to give the α-methyl-β-keto ester 1z as colorless oil (503.0 mg, 61% yield).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.38 (d, J=7.9 Hz, 2H), 7.31 (t, J=7.5 Hz, 2H), 7.26-7.21 (m, 1H), 6.59 (d, J=15.9 Hz, 1H), 6.25 (dtd, J=15.9, 6.0, 1.0 Hz, 1H), 4.13 (d, J=6.1 Hz, 2H), 3.78-3.74 (m, 2H), 3.73 (d, J=1.1 Hz, 3H), 3.60 (qd, J=7.2, 0.9 Hz, 1H), 2.89-2.79 (m, 2H), 1.36 (dd, J=7.2, 1.3 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.3, 171.0, 136.8, 132.7, 128.7, 127.9, 126.6, 125.9, 71.9, 65.1, 53.3, 52.6, 41.7, 12.7.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1257.

3. Optimization of Enantioselective CDC Reaction

entry deviation from standard condition yield (%) e.r. 1 none 65 92:8 2 w/o pre-complexation between L1 and Cu(OTf)₂ 35~67 56:44~90:10 3 w/o MS 4Å 10 87:13 4 MS 3Å instead of MS 4Å 68 90:10 5 ClCH₂CH₂Cl instead of CH₂Cl₂ 68 90:10 6 MeCN instead of CH₂Cl₂ 45 74:26 7 CH₂Cl₂/MeCN instead of CH₂Cl₂ 55 75:25 8 CH₂Cl₂/Toluene instead of CH₂Cl₂ 28 86:14 9 CH₂Cl₂/THF instead of CH₂Cl₂ 10 85:15 10 Cl instead of OTf 45 52:48 11 OAc instead of OTf 49 56:44 12 ClO₄ instead of OTf 65 69:31 13 SbF₆ instead of OTf 68 74:26 14 PF₆ instead of OTf 70 81:19 15 BF₄ instead of OTf 69 85:15

To an oven dried 20 mL reaction vial equipped with a magnetic stir bar under N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 150 mg of 4 Å molecular sieve (powder), 1.0 mL of L1.Cu(OTf)₂ (0.02 M in CH₂Cl₂). The solution then was stirred for 1 h. The β-keto ester 1a was dissolved in 0.5 mL of CH₂Cl₂ and was added, and the solution stirred at ambient temperature for 30 minutes. The reaction was then cooled to −30° C., and DDQ (59.0 mg, 0.26 mmol) dissolved in 4.0 mL of DCM was added over 1 h by syringe pump. The reaction was stirred for 2 h at −30° C., and then 1.0 mL of Et₃N was added to quench the reaction. The solution was filtered over a pad of silica (4 cm) with ethyl acetate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:5) to give the tetrahydropyran-4-one 2a.

4. General Procedure for Enantioselective CDC Reaction

To an oven dried 20 mL reaction vial equipped with a magnetic stir bar under N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 250 mg of 4 Å molecular sieve (powder), 1.0 mL of L3.Cu(OTf)₂ (0.02 M in CH₂Cl₂), and 4.0 mL of CH₂Cl₂. The solution then was stirred for 1 h. The corresponding β-keto ester was dissolved in 1.0 mL of CH₂Cl₂ and was added, and the solution stirred at ambient temperature for 30 mins. The reaction was then cooled to −70° C., and DDQ (59.0 mg, 0.26 mmol) dissolved in 4.0 mL of DCM was added over 1 h by syringe pump. The reaction was stirred for 12 h at −70° C., and then 1.0 mL of Et₃N was added to quench the reaction. The solution was filtered over a pad of silica (4 cm) with ethyl acetate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4˜1:6) to give the corresponding tetrahydropyran-4-ones 2. (The tetrahydropyran-4-ones 2 were isolated with the corresponding enol tautomers 2′.)

White solid. (43.3 mg, 83% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39-7.36 (m, 2H), 7.35-7.30 (m, 2H), 7.29-7.25 (m, 1H), 6.72 (d, J=15.9 Hz, 1H), 6.17 (dd, J=15.9, 6.6 Hz, 1H), 4.58 (dd, J=10.1, 6.7 Hz, 1H), 4.38 (ddd, J=11.6, 7.3, 1.6 Hz, 1H), 3.87 (td, J=11.9, 2.8 Hz, 1H), 3.74 (s, 3H), 3.48 (d, J=10.1 Hz, 1H), 2.70 (ddd, J=14.4, 12.4, 7.3 Hz, 1H), 2.51 (dt, J=14.6, 2.0 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.3, 168.0, 136.1, 133.7, 128.8, 128.5, 126.9, 125.8, 80.2, 66.5, 63.6, 52.4, 41.6.

HRMS (ESI) calculated for C1411604 [M+Na]⁺: 283.0946. Found: 283.0946.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.3 min (major), 2.9 min (minor).

Yellow solid. (38.5 mg, 70% yield, 89:11 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.40-7.35 (m, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.29-7.22 (m, 1H), 6.72 (d, J=15.9 Hz, 1H), 6.18 (dd, J=15.9, 6.6 Hz, 1H), 4.63-4.51 (m, 1H), 4.37 (ddd, J=11.5, 7.3, 1.5 Hz, 1H), 4.29-4.13 (m, 2H), 3.87 (td, J=11.9, 2.9 Hz, 1H), 3.45 (dd, J=10.2, 1.0 Hz, 1H), 2.70 (ddd, J=14.5, 12.6, 7.6 Hz, 1H), 2.50 (ddd, J=14.6, 2.9, 1.6 Hz, 1H), 1.24 (td, J=7.1, 5.1 Hz, 3H) for keto form; 12.29 (s, 1H), 7.42-7.35 (m, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.29-7.22 (m, 1H), 6.51 (d, J=16.0 Hz, 1H), 6.29 (dd, J=16.0, 5.6 Hz, 1H), 5.11 (d, J=5.6 Hz, 1H), 4.29-4.12 (m, 2H), 4.02-3.92 (m, 1H), 3.84-3.78 (m, 1H), 2.64-2.53 (m, 1H), 2.28 (dt, J=17.9, 3.9 Hz, 1H), 1.24 (td, J=7.1, 5.1 Hz, 3H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 170.7, 170.7, 167.5, 136.8, 136.1, 133.7, 133.1, 128.7, 128.7, 128.6, 128.4, 127.9, 126.9, 126.7, 125.9, 99.3, 80.2, 71.2, 66.5, 63.6, 61.4, 60.6, 59.0, 41.6, 29.1, 14.3, 14.3.

HRMS (ESI) calculated for C₁₆H₁₈O₄[M+Na]⁺: 297.1103. Found: 297.1105.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.9 min (minor), 3.2 min (major).

Colorless oil. (33.5 mg, 55% yield, 90:10 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.38 (t, J=6.4 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.29-7.22 (m, 1H), 6.71 (d, J=15.9 Hz, 1H), 6.19 (dd, J=15.9, 6.6 Hz, 1H), 4.53 (ddd, J=10.1, 6.6, 0.9 Hz, 1H), 4.35 (ddd, J=11.5, 7.3, 1.6 Hz, 1H), 3.85 (td, J=11.9, 2.9 Hz, 1H), 3.34 (d, J=10.7 Hz, 4H), 2.73-2.63 (m, 1H), 2.47 (ddd, J=14.7, 2.9, 1.7 Hz, 1H), 1.45 (s, 9H) for keto form; 12.43 (s, 1H), 7.38 (t, J=6.4 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.29-7.23 (m, 1H), 6.52 (d, J=15.9 Hz, 1H), 6.27 (dd, J=15.9, 5.9 Hz, 1H), 5.02 (d, J=5.8 Hz, 1H), 4.00-3.92 (m, 1H), 3.82-3.75 (m, 1H), 2.58-2.50 (m, 1H), 2.27 (dt, J=17.8, 3.9 Hz, 1H), 1.44 (s, 9H) for enol form.

HRMS (ESI) calculated for C₁₈H₂₂O₄ [M+Na]⁺: 325.1416. Found: 325.1410.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.4 min (major), 2.8 min (minor).

White solid. (35.8 mg, 56% yield, 84:16 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.33-7.27 (m, 7H), 7.27-7.22 (m, 3H), 6.65 (dd, J=15.9, 1.0 Hz, 1H), 6.13 (dd, J=15.9, 6.7 Hz, 1H), 5.19 (s, 2H), 4.58 (dd, J=10.2, 6.7 Hz, 1H), 4.37 (ddd, J=11.4, 7.3, 1.2 Hz, 1H), 3.87 (td, J=11.9, 2.8 Hz, 1H), 3.51 (d, J=10.3 Hz, 1H), 2.75-2.63 (m, 1H), 2.50 (ddd, J=14.8, 2.8, 1.6 Hz, 1H).

HRMS (ESI) calculated for C₂₁H₂₀O₄ [M+Na]⁺: 359.1259. Found: 359.1260.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=210 nm): 6.5 min (major), 6.8 min (minor).

White solid. (42.3 mg, 69% yield)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.84 (d, J=7.6 Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.35-7.09 (m, 5H), 6.71 (d, J=15.9 Hz, 1H), 6.13 (dd, J=16.0, 6.0 Hz, 1H), 4.89 (dd, J=9.7, 6.1 Hz, 1H), 4.53-4.32 (m, 2H), 3.96 (td, J=11.9, 3.0 Hz, 1H), 2.89-2.76 (m, 1H), 2.55 (d, J=14.7 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 203.7, 196.4, 137.6, 136.2, 133.7, 133.2, 128.9, 128.7, 128.5, 128.2, 126.8, 126.3, 80.3, 66.4, 64.1, 42.3.

HRMS (ESI) calculated for C₂₀H₁₈O₃ [M+Na]⁺: 329.1154. Found: 329.1150.

Yellow solid. (34.8 mg, 60% yield, 78:22 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.31 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.65 (d, J=15.9 Hz, 1H), 6.03 (dd, J=15.9, 6.8 Hz, 1H), 4.55 (dd, J=9.8, 7.1 Hz, 1H), 4.37 (dd, J=10.9, 6.8 Hz, 1H), 3.85 (td, J=12.0, 2.6 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.47 (d, J=10.1 Hz, 1H), 2.69 (td, J=13.4, 12.4, 7.4 Hz, 1H), 2.50 (d, J=14.4 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.4, 168.0, 159.9, 133.4, 128.8, 128.2, 123.5, 114.2, 80.5, 66.4, 63.7, 55.5, 52.4, 41.6.

HRMS (ESI) calculated for C₁₆H₁₈O₅ [M+Na]⁺: 313.1052. Found: 313.1055.

Chiral SFC (Chiralpak IG-3, 5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 9.1 min (major), 8.5 min (minor).

Yellow oil. (45.1 mg, 78% yield, 96:4 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.24 (t, J=7.9 Hz, 1H), 6.98 (ddt, J=9.0, 7.7, 1.2 Hz, 1H), 6.92 (dt, J=11.9, 2.0 Hz, 1H), 6.82 (tdd, J=8.1, 2.6, 0.9 Hz, 1H), 6.68 (d, J=15.9 Hz, 1H), 6.16 (dd, J=15.9, 6.6 Hz, 1H), 4.58 (dd, J=10.6, 7.0 Hz, 1H), 4.38 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.90-3.84 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.47 (d, J=10.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.54-2.45 (m, 1H) for keto form; 12.21 (s, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.98 (ddt, J=9.0, 7.7, 1.2 Hz, 1H), 6.92 (dt, J=11.9, 2.0 Hz, 1H), 6.82 (tdd, J=8.1, 2.6, 0.9 Hz, 1H), 6.47 (d, J=16.0 Hz, 1H), 6.28 (dd, J=16.0, 5.4 Hz, 1H), 5.12 (d, J=5.2 Hz, 1H), 4.01-3.92 (m, 1H), 3.82 (s, 3H), 3.80-3.78 (m, 1H), 3.74 (s, 3H), 2.63-2.55 (m, 1H), 2.27 (dt, J=18.0, 3.5 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.1, 167.8, 137.4, 133.4, 129.6, 126.0, 119.4, 113.9, 112.1, 80.0, 66.4, 63.4, 55.3, 52.3, 41.5 for keto form; 171.0, 170.7, 159.8, 138.1, 132.9, 129.6, 128.7, 119.3, 113.6, 111.9, 99.0, 70.7, 58.6, 51.6, 29.0 for enol form.

HRMS (ESI) calculated for C₁₆H₁₈O₅ [M+Na]⁺: 313.1052. Found: 313.1049.

Chiral SFC (Chiralpak ID-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.1 min (major), 1.7 min (minor).

Yellow oil. (40.9 mg, 70% yield, 92:8 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.37 (m, 1H), 7.25-7.20 (m, 1H), 7.02 (d, J=16.0 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.20 (dd, J=16.1, 6.7 Hz, 1H), 4.58 (dd, J=10.5, 6.3 Hz, 1H), 4.38 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.89-3.85 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.49 (d, J=10.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.50 (dt, J=14.7, 2.6 Hz, 1H) for keto form; 12.22 (s, 1H), 7.48-7.37 (m, 1H), 7.25-7.20 (m, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.82 (d, J=16.1 Hz, 1H), 6.29 (dd, J=16.1, 5.5 Hz, 1H), 5.12 (d, J=5.5 Hz, 1H), 4.06-3.95 (m, 1H), 3.84 (s, 3H), 3.83-3.78 (m, 1H), 3.74 (s, 3H), 2.63-2.54 (m, 1H), 2.27 (dt, J=18.0, 3.5 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.5, 171.2, 170.7, 168.0, 157.2, 157.0, 129.5, 129.0, 129.0, 128.9, 128.2, 127.5, 127.4, 127.2, 126.4, 125.9, 125.1, 120.8, 120.7, 111.0, 111.0, 99.5, 80.7, 71.3, 66.4, 63.8, 58.7, 55.6, 52.3, 51.6, 41.6, 29.1.

HRMS (ESI) calculated for C16H1805[M+Na]⁺: 313.1052. Found: 313.1053.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 4.4 min (major), 3.6 min (minor) and 4.9 min (major), 6.5 min (minor) (keto/enol forms were not assigned).

White solid. (46.3 mg, 84% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.31-7.24 (m, 2H), 7.13 (d, J=7.7 Hz, 2H), 6.68 (d, J=15.9 Hz, 1H), 6.12 (dd, J=15.9, 6.7 Hz, 1H), 4.57 (dd, J=10.8, 6.8 Hz, 1H), 4.37 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.90-3.83 (m, 1H), 3.73 (s, 3H), 3.47 (d, J=10.1 Hz, 1H), 2.75-2.65 (m, 1H), 2.53-2.46 (m, 1H), 2.34 (s, 3H) for keto form; 12.21 (s, 1H), 7.31-7.24 (m, 2H), 7.13 (d, J=7.7 Hz, 2H), 6.46 (d, J=16.0 Hz, 1H), 6.24 (dd, J=16.0, 5.4 Hz, 1H), 5.11 (d, J=5.5 Hz 1H), 3.99-3.91 (m, 1H), 3.82-3.77 (m, 1H), 3.73 (s, 3H), 2.63-2.54 (m, 1H), 2.34 (s, 3H), 2.26 (dt, J=18.0, 3.7 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 171.2, 170.8, 168.0, 138.4, 137.9, 133.9, 133.7, 133.3, 133.1, 129.5, 129.4, 127.5, 126.8, 126.7, 124.7, 99.3, 80.3, 70.9, 66.5, 63.7, 58.7, 52.4, 51.7, 41.6, 29.1, 21.4, 21.4.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1103.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.3 min (major), 2.0 min (minor) and 2.6 min (major), 2.9 min (minor) (keto/enol forms were not assigned).

White solid. (39.2 mg, 71% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.24-7.16 (m, 3H), 7.12-7.04 (m, 1H), 6.68 (d, J=15.9 Hz, 1H), 6.15 (dd, J=15.9, 6.7 Hz, 1H), 4.57 (ddd, J=10.2, 6.7, 1.1 Hz, 1H), 4.37 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.86 (td, J=12.0, 2.9 Hz, 1H), 3.74 (s, 3H), 3.47 (d, J=10.2 Hz, 1H), 2.74-2.66 (m, 1H), 2.54-2.48 (m, 1H), 2.35 (s, 3H) for keto form; 12.21 (s, 1H), 7.24-7.16 (m, 3H), 7.12-7.04 (m, 1H), 6.47 (d, J=16.0 Hz, 1H), 6.28 (dd, J=16.0, 5.4 Hz, 1H), 5.12 (d, J=5.3 Hz, 1H), 4.02-3.91 (m, 1H), 3.83-3.78 (m, 1H), 3.74 (s, 3H), 2.64-2.54 (m, 1H), 2.35 (s, 3H), 2.26 (dt, J=18.0, 3.5 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 171.0, 170.7, 167.9, 138.2, 138.2, 136.5, 135.9, 133.7, 133.1, 129.1, 128.6, 128.5, 128.5, 128.2, 127.5, 127.4, 125.5, 123.9, 123.8, 99.1, 80.1, 70.7, 66.3, 63.5, 58.5, 52.3, 51.6, 41.5, 29.0, 21.4, 21.4.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1103.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.9 min (major), 2.6 min (minor) and 6.5 min (major), 16.0 min (minor) (keto/enol forms were not assigned).

Yellow oil. (44.4 mg, 81% yield, 96:4 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.42-7.38 (m, 1H), 7.20-7.10 (m, 3H), 6.93 (d, J=15.8 Hz, 1H), 6.04 (dd, J=15.8, 6.7 Hz, 1H), 4.60 (dd, J=10.2, 6.7 Hz, 1H), 4.39 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.90-3.84 (m, 1H), 3.75 (s, 3H), 3.49 (d, J=10.2 Hz, 1H), 2.76-2.66 (m, 1H), 2.54-2.48 (m, 1H), 2.33 (s, 3H) for keto form; 12.21 (s, 1H), 7.44-7.42 (m, 1H), 7.20-7.10 (m, 3H), 6.74 (d, J=15.8 Hz, 1H), 6.13 (dd, J=15.8, 5.6 Hz, 1H), 5.12 (d, J=5.5 Hz, 1H), 4.04-3.96 (m, 1H), 3.84-3.80 (m, 1H), 3.75 (s, 3H), 2.64-2.55 (m, 1H), 2.33 (s, 3H), 2.29 (dt, J=18.0, 3.7 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 171.1, 170.8, 168.0, 136.1, 136.0, 135.6, 135.4, 131.8, 131.1, 130.4, 130.4, 130.0, 128.3, 127.8, 127.4, 126.3, 126.3, 126.1, 126.0, 99.3, 80.4, 71.2, 66.5, 63.7, 58.8, 52.4, 51.7, 41.6, 29.1, 19.9, 19.9.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1101.

Chiral SFC (Chiralpak IC-3, 1.5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 5.6 min (major), 3.7 min (minor) and 6.5 min (major), 7.3 min (minor) (keto/enol forms were not assigned).

White solid. (40.2 mg, 59% yield, 94:6 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.41 (m, 2H), 7.27-7.21 (m, 2H), 6.66 (d, J=15.9 Hz, 1H), 6.16 (dd, J=15.9, 6.5 Hz, 1H), 4.57 (dd, J=10.7, 6.1 Hz, 1H), 4.38 (ddd, J=11.7, 7.4, 1.7 Hz, 1H), 3.90-3.84 (m, 1H), 3.74 (s, 3H), 3.46 (d, J=10.3 Hz, 1H), 2.76-2.66 (m, 1H), 2.51 (ddd, J=14.6, 2.6, 1.6 Hz, 1H) for keto form; 12.20 (s, 1H), 7.48-7.41 (m, 2H), 7.27-7.21 (m, 2H), 6.45 (d, J=16.0 Hz, 1H), 6.28 (dd, J=16.0, 5.3 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 3.99-3.91 (m, 1H), 3.84-3.78 (m, 1H), 3.74 (s, 3H), 2.64-2.54 (m, 1H), 2.28 (dt, J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 171.0, 170.9, 167.9, 135.7, 135.0, 132.4, 131.9, 131.8, 131.8, 129.4, 128.4, 128.3, 126.6, 122.4, 121.7, 99.0, 80.0, 70.8, 66.5, 63.5, 58.9, 52.4, 51.8, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅BrO₄ [M+Na]⁺: 361.0051. Found: 361.0047.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 5.7 min (major), 5.2 min (minor).

White solid. (37.5 mg, 55% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.57-7.50 (m, 1H), 7.42-7.35 (m, 1H), 7.29 (t, J=8.3 Hz, 1H), 7.19 (td, J=7.8, 1.7 Hz, 1H), 6.65 (d, J=15.9 Hz, 1H), 6.17 (dd, J=15.9, 6.4 Hz, 1H), 4.58 (ddd, J=10.3, 6.4, 1.2 Hz, 1H), 4.38 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.89-3.83 (m, 1H), 3.76 (s, 3H), 3.45 (d, J=10.3 Hz, 1H), 2.76-2.65 (m, 1H), 2.54-2.48 (m, 1H) for keto form; 12.20 (s, 1H), 7.57-7.50 (m, 1H), 7.42-7.35 (m, 1H), 7.29 (t, J=8.3 Hz, 1H), 7.19 (td, J=7.8, 1.7 Hz, 1H), 6.44 (d, J=16.0 Hz, 1H), 6.29 (dd, J=16.0, 5.3 Hz, 1H), 5.11 (d, J=5.2 Hz, 1H), 3.97-3.91 (m, 1H), 3.83-3.79 (m, 1H), 3.75 (s, 3H), 2.63-2.54 (m, 1H), 2.27 (dt, J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.0, 171.0, 171.0, 167.9, 138.9, 138.2, 132.0, 131.5, 131.3, 130.8, 130.3, 130.2, 130.2, 129.7, 129.6, 127.4, 125.6, 125.4, 123.0, 122.9, 99.0, 79.8, 70.7, 66.5, 63.4, 58.9, 52.5, 51.8, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅BrO₄ [M+Na]⁺: 361.0051. Found: 361.0044.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 4.9 min (major), 4.1 min (minor).

White solid. (40.1 mg, 68% yield, 96:4 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.38 (s, 1H), 7.29-7.20 (m, 3H), 6.68 (d, J=15.9 Hz, 1H), 6.19 (dd, J=15.9, 6.4 Hz, 1H), 4.59 (ddd, J=10.3, 6.4, 1.2 Hz, 1H), 4.40 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.91-3.85 (m, 1H), 3.77 (s, 3H), 3.47 (d, J=10.3 Hz, 1H), 2.77-2.67 (m, 1H), 2.53 (ddd, J=14.7, 2.9, 1.6 Hz, 1H) for keto form; 12.22 (s, 1H), 7.40 (s, 1H), 7.29-7.20 (m, 3H), 6.47 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 5.3 Hz, 1H), 5.13 (d, J=5.2 Hz, 1H), 4.00-3.93 (m, 1H), 3.85-3.81 (m, 1H), 3.77 (s, 3H), 2.65-2.56 (m, 1H), 2.29 (dt, J=18.0, 3.6 Hz, 2H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.0, 171.0, 171.0, 167.9, 138.7, 137.9, 134.8, 134.7, 132.2, 131.6, 130.2, 130.0, 129.9, 128.4, 127.9, 127.3, 126.8, 126.7, 125.1, 125.0, 99.0, 79.8, 70.8, 66.5, 63.4, 58.9, 52.5, 51.8, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅ClO₄[M+Na]⁺: 317.0557. Found: 317.0549.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 4.0 min (major), 3.3 min (minor).

Yellow oil. (34.0 mg, 58% yield, 97:3 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.50-7.47 (m, 1H), 7.35 (d, J=7.0 Hz, 1H), 7.25-7.16 (m, 2H), 7.09 (d, J=15.9 Hz, 1H), 6.15 (dd, J=15.9, 6.4 Hz, 1H), 4.62 (dd, J=10.3, 6.4 Hz, 1H), 4.39 (dd, J=11.4, 7.1 Hz, 1H), 3.91-3.85 (m, 1H), 3.77 (s, 3H), 3.48 (d, J=10.4 Hz, 1H), 2.77-2.67 (m, 1H), 2.54-2.48 (m, 1H) for keto form; 12.22 (s, 1H), 7.54-7.50 (m, 1H), 7.35 (d, J=7.0 Hz, 1H), 7.25-7.16 (m, 2H), 6.91 (dd, J=16.0, 1.5 Hz, 1H), 6.22 (dd, J=15.9, 5.6 Hz, 1H), 5.14 (d, J=5.5 Hz, 1H), 4.03-3.96 (m, 1H), 3.85-3.81 (m, 1H), 3.76 (s, 3H), 2.63-2.54 (m, 1H), 2.30 (dt, J=17.9, 3.7 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 171.0, 170.9, 167.9, 135.2, 134.4, 133.6, 133.3, 131.4, 129.9, 129.8, 129.5, 129.4, 128.9, 128.8, 127.2, 127.1, 127.0, 99.0, 79.9, 71.1, 66.6, 63.6, 59.0, 52.5, 51.7, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅ClO₄ [M+Na]⁺: 317.0557. Found: 317.0554.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.7 min (major), 2.4 min (minor).

Yellow solid. (48.1 mg, 77% yield, 94:6 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.87-7.72 (m, 4H), 7.58 (dd, J=8.6, 1.7 Hz, 1H), 7.51-7.41 (m, 2H), 6.88 (d, J=15.9 Hz, 1H), 6.30 (dd, J=15.9, 6.6 Hz, 1H), 4.65 (ddd, J=10.2, 6.6, 1.1 Hz, 1H), 4.40 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.92-3.86 (m, 1H), 3.75 (s, 3H), 3.53 (d, J=10.2 Hz, 1H), 2.77-2.68 (m, 1H), 2.56-2.48 (m, 1H) for keto form; 12.25 (s, 1H), 7.87-7.72 (m, 4H), 7.62 (dd, J=8.6, 1.8 Hz, 1H), 7.51-7.41 (m, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.42 (dd, J=15.9, 5.4 Hz, 1H), 5.18 (d, J=5.3 Hz, 1H), 4.01 (ddd, J=11.7, 9.6, 4.3 Hz, 1H), 3.86-3.81 (m, 1H), 3.76 (s, 3H), 2.66-2.56 (m, 1H), 2.30 (dt, J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 171.1, 170.9, 168.0, 134.2, 133.8, 133.7, 133.6, 133.5, 133.4, 133.2, 128.9, 128.4, 128.4, 128.2, 128.1, 127.8, 127.8, 127.4, 126.9, 126.6, 126.5, 126.4, 126.1, 126.1, 123.7, 123.6, 99.2, 80.3, 71.0, 66.5, 63.6, 58.8, 52.4, 51.8, 41.7, 29.1.

HRMS (ESI) calculated for C19H₁₈O₄ [M+Na]⁺: 333.1103. Found: 333.1101.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 10.6 min (major), 9.3 min (minor).

Yellow solid. (49.4 mg, 80% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 8.05 (d, J=8.0 Hz, 1H), 7.88-7.84 (m, 1H), 7.80 (t, J=8.3 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.55-7.42 (m, 4H), 6.20 (dd, J=15.6, 6.6 Hz, 1H), 4.72 (ddd, J=10.4, 6.6, 1.2 Hz, 1H), 4.43 (ddd, J=11.6, 7.3, 1.6 Hz, 1H), 3.94-3.89 (m, 1H), 3.76 (s, 3H), 3.56 (d, J=10.3 Hz, 1H), 2.79-2.70 (m, 1H), 2.54 (ddd, J=14.7, 2.8, 1.6 Hz, 1H) for keto form; 12.26 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88-7.84 (m, 1H), 7.80 (t, J=8.3 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.55-7.42 (m, 3H), 7.30 (d, J=15.7 Hz, 1H), 6.30 (dd, J=15.7, 5.5 Hz, 1H), 5.22 (d, J=5.4 Hz, 1H), 4.13-4.04 (m, 1H), 3.89-3.85 (m, 1H), 3.79 (s, 3H), 2.68-2.59 (m, 1H), 2.34 (dt, J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 171.2, 170.9, 168.1, 134.7, 134.0, 133.7, 133.7, 131.8, 131.3, 131.3, 131.2, 130.4, 129.1, 128.7, 128.2, 126.4, 126.2, 126.1, 125.9, 125.7, 125.7, 124.3, 124.1, 123.8, 99.3, 80.4, 71.3, 66.6, 63.7, 59.0, 52.4, 51.7, 41.6, 29.2.

HRMS (ESI) calculated for C₁₉H₁₈O₄ [M+Na]⁺: 333.1103. Found: 333.1101.

Chiral SFC (Chiralpak ID-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.6 min (major), 2.0 min (minor).

White solid. (47.5 mg, 87% yield, 97:3 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.33 (t, J=7.6 Hz, 2H), 7.27-7.21 (m, 3H), 6.55 (s, 1H), 4.48 (d, J=10.3 Hz, 1H), 4.37 (ddd, J=11.5, 7.4, 1.6 Hz, 1H), 3.87 (td, J=11.8, 2.8 Hz, 1H), 3.72 (s, 3H), 3.67 (d, J=10.7 Hz, 1H), 2.74-2.62 (m, 1H), 2.50 (ddd, J=14.9, 2.8, 1.5 Hz, 1H), 1.95 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.7, 167.9, 136.8, 134.3, 130.1, 129.1, 128.3, 127.2, 85.7, 66.4, 61.9, 52.4, 41.5, 13.0.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1104.

Chiral SFC (Chiralpak ID-3, 1% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 4.0 min (major), 3.3 min (minor).

White foam solid. (49.7 mg, 55% yield, 87:13 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.99 (dd, J=8.3, 3.6 Hz, 1H), 7.77 (dd, J=8.4, 6.2 Hz, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.25 (m, 1H), 7.22 (d, J=8.2 Hz, 2H), 6.79 (d, J=16.1 Hz, 1H), 6.23 (dd, J=16.1, 6.6 Hz, 1H), 4.58 (dd, J=10.2, 6.6 Hz, 1H), 4.39 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.87 (td, J=11.9, 2.8 Hz, 1H), 3.75 (s, 3H), 3.50 (d, J=10.2 Hz, 1H), 2.75-2.67 (m, 1H 2.52 (dq, J=14.6, 1.7 Hz, 1H), 2.34 (s, 3H) for keto form; 12.21 (s, 1H), 7.99 (dd, J=8.3, 3.6 Hz, 1H), 7.77 (dd, J=8.4, 6.2 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.25 (m, 1H), 7.22 (d, J=8.2 Hz, 2H), 6.58 (d, J=16.2 Hz, 1H), 6.36 (dd, J=16.2, 5.4 Hz, 1H), 5.13 (d, J=5.5 Hz, 1H), 4.02-3.94 (m, 1H), 3.84-3.79 (m, 1H), 3.75 (s, 3H), 2.63-2.55 (m, 1H), 2.34 (s, 3H), 2.30 (dt, J=18.0, 3.7 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 171.1, 170.9, 168.0, 145.3, 145.2, 135.6, 135.6, 135.3, 135.2, 130.1, 130.1, 129.8, 129.1, 128.9, 127.0, 126.9, 125.2, 125.1, 125.0, 124.5, 124.4, 123.8, 123.7, 123.6, 120.5, 120.4, 120.0, 119.3, 113.9, 113.9, 99.0, 80.4, 71.2, 66.5, 63.6, 58.9, 52.5, 51.8, 41.7, 29.1, 21.7.

HRMS (ESI) calculated for C₂₄H₂₃NO₆S [M+Na]⁺: 476.1144. Found: 476.1138.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 5.4 min (minor), 5.9 min (major) and 10.5 min (major), 12.1 min (minor) (keto/enol forms were not assigned).

Yellow oil. (36.5 mg, 69% yield, 88:12 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.19 (d, J=5.0 Hz, 1H), 7.02-6.93 (m, 2H), 6.83 (d, J=15.7 Hz, 1H), 6.00 (dd, J=15.7, 6.6 Hz, 1H), 4.54 (ddd, J=10.3, 6.6, 1.2 Hz, 1H), 4.36 (ddd, J=11.6, 7.2, 1.7 Hz, 1H), 3.84 (td, J=11.8, 2.8 Hz, 1H), 3.75 (s, 3H), 3.46 (d, J=10.2 Hz, 1H), 2.74-2.65 (m, 1H), 2.49 (ddd, J=14.7, 2.8, 1.7 Hz, 1H) for keto form; 12.20 (s, 1H), 7.18-7.15 (m, 1H), 7.02-6.93 (m, 2H), 6.62 (d, J=15.8 Hz, 1H), 6.13 (dd, J=15.8, 5.4 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 3.99-3.91 (m, 1H), 3.81-3.78 (m, 1H), 3.75 (s, 3H), 2.63-2.54 (m, 1H), 2.25 (ddd, J=18.0, 4.3, 2.8 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 171.0, 170.9, 167.9, 141.9, 141.0, 128.2, 127.6, 127.5, 127.1, 126.8, 126.3, 126.3, 125.4, 125.1, 124.7, 99.0, 79.9, 70.6, 66.4, 63.5, 58.7, 52.4, 51.8, 41.6, 29.0.

HRMS (ESI) calculated for C₁₃H₁₄O₄ [M+Na]⁺: 289.0510. Found: 289.0507.

Chiral SFC (Chiralpak IG-3, 30% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.1 min (minor), 2.4 min (major).

Yellow solid. (28.8 mg, 50% yield, 91:9 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.26-7.21 (m, 1H), 6.73 (dd, J=15.6, 10.5 Hz, 1H), 6.60 (d, J=15.6 Hz, 1H), 6.50 (dd, J=15.2, 10.4 Hz, 1H), 5.77 (dd, J=15.2, 6.7 Hz, 1H), 4.51 (ddd, J=10.2, 6.6, 1.1 Hz, 1H), 4.35 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.84 (td, J=11.9, 2.9 Hz, 1H), 3.76 (s, 3H), 3.43 (d, J=10.2 Hz, 1H), 2.73-2.63 (m, 1H), 2.49 (ddd, J=14.6, 2.9, 1.7 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.3, 168.0, 136.9, 134.8, 134.0, 129.3, 128.8, 128.1, 127.6, 126.7, 79.9, 66.5, 63.6, 52.4, 41.6.

HRMS (ESI) calculated for C₁₇H₁₈O₄ [M+Na]⁺: 309.1103. Found: 309.1100.

Chiral SFC (Chiralpak IG-3, 30% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 4.0 min (minor), 5.3 min (major).

White solid. (26.4 mg, 50% yield, 91:9 e.r., reaction for 20 h at −30° C.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.32 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 4.85 (d, J=10.4 Hz, 1H), 4.40 (ddd, J=11.6, 7.5, 1.5 Hz, 1H), 3.91 (td, J=12.2, 2.7 Hz, 1H), 3.80 (s, 3H), 3.67 (d, J=11.1 Hz, 1H), 3.61 (s, 3H), 2.84-2.72 (m, 1H), 2.58-2.50 (m, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.6, 167.9, 160.0, 130.8, 128.3, 114.2, 81.7, 66.8, 65.0, 55.4, 52.2, 41.7.

HRMS (ESI) calculated for C₁₄H₁₆O₅ [M+Na]⁺: 287.0895. Found: 287.0897.

Chiral SFC (Chiralpak IG-3, 20% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.1 min (major), 1.7 min (minor).

White solid. (29.4 mg, 50% yield, 89:11 e.r., reaction for 4 h at −30° C.)

¹H NMR (500 MHz, CDCl₃): δ ppm 6.95-6.88 (m, 2H), 6.86-6.78 (m, 1H), 4.86 (d, J=10.4 Hz, 1H), 4.41 (ddd, J=11.6, 7.4, 1.5 Hz, 1H), 3.95-3.90 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.67 (d, J=10.4 Hz, 1H), 3.62 (s, 3H), 2.84-2.72 (m, 1H), 2.54 (ddd, J=14.6, 2.8, 1.5 Hz, 1H) for keto form; 12.25 (s, 1H), 6.95-6.88 (m, 2H), 6.86-6.78 (m, 1H), 5.45 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.74-3.70 (m, 2H), 3.59 (s, 3H), 2.64-2.58 (m, 1H), 2.34 (dt, J=18.0, 4.0 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 171.0, 170.9, 167.8, 149.3, 149.1, 148.9, 148.8, 133.5, 131.1, 120.6, 119.3, 111.5, 111.0, 110.3, 109.7, 99.3, 81.7, 73.1, 66.7, 64.9, 58.5, 55.9, 55.9, 52.1, 51.5, 41.5, 29.0.

HRMS (ESI) calculated for C₁₅H₁₈O₆ [M+Na]⁺: 317.1001. Found: 317.1002.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.9 min (major), 2.6 min (minor).

Colorless oil. (36.3 mg, 83% yield, 91:9 e.r., reaction for 45 h at −30° C.)

¹H NMR (500 MHz, CDCl₃): δ ppm 6.61 (s, 2H), 4.98-4.79 (m, 1H), 4.43 (ddd, J=11.6, 7.4, 1.5 Hz, 1H), 3.94-3.89 (m, 1H), 3.86 (s, 6H), 3.83 (s, 3H), 3.69-3.64 (m, 4H), 2.84-2.73 (m, 1H), 2.58-2.53 (m, 1H) for keto form; 12.26 (s, 1H), 6.52 (s, 2H), 5.42 (s, 1H), 3.85 (s, 6H), 3.84 (s, 3H), 3.79-3.70 (m, 2H), 3.61 (s, 3H), 2.62-2.58 (m, 1H), 2.44-2.37 (m, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 171.2, 171.1, 167.9, 153.5, 153.2, 138.4, 137.9, 136.8, 134.3, 105.6, 103.8, 102.5, 99.3, 81.9, 73.8, 66.8, 65.0, 61.0, 59.3, 56.3, 56.3, 52.3, 51.7, 41.6, 29.2.

HRMS (ESI) calculated for C₁₆H₂₀O₇ [M+Na]⁺: 347.1107. Found: 347.1110.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.8 min (major), 3.7 min (minor) and 3.1 min (major), 4.2 min (minor) (keto/enol forms were not assigned).

White solid (35.5 mg, 65% yield, >20:1 dr, 96:4 er).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.36 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.29-7.23 (m, 1H), 6.71 (d, J=15.9 Hz, 1H), 6.01 (dd, J=15.9, 6.1 Hz, 1H), 4.82 (dd, J=6.1, 1.2 Hz, 1H), 4.35 (ddd, J=11.6, 7.4, 2.5 Hz, 1H), 3.90 (td, J=11.4, 3.7 Hz, 1H), 3.79 (s, 3H), 2.81 (ddd, J=15.2, 11.4, 7.4 Hz, 1H), 2.44 (ddd, J=15.2, 3.7, 2.4 Hz, 1H), 1.41 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 205.6, 171.2, 136.3, 134.0, 128.7, 128.3, 126.8, 123.2, 81.7, 66.1, 63.3, 52.6, 38.2, 15.1.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1108.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 2.9 min (major), 5.6 min (minor).

The stereochemistry of the product was determined by NOESY experiments (data not shown).

CDC Reaction of Unsuccessful Substrates

Under optimized conditions, we examined a few more substrates 1u-1y (as shown above). We observed that reaction of 1u, 1v and 1y gave trace amount of desired products after 24 hours even upon warming to room temperature, and starting materials were isolated in >85% yield. The reaction of allyl ether 1w provided overoxidized side products, but the desired product was not obtained. Furthermore, we attempted to enantioselectivity access tetrahydrofurans using our optimized reaction conditions; however, 1x did not provide the desired product upon extensive reaction testing. In the reaction of 1x, cyclic acetal compounds S2x were obtained (see below).

Pale yellow solid. (38.4 mg, 74% yield, spectra data for the major compound was attached.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.46-7.40 (m, 2H), 7.38-7.29 (m, 3H), 6.89 (d, J=16.0 Hz, 1H), 6.23 (dd, J=16.0, 6.3 Hz, 1H), 6.03 (d, J=6.2 Hz, 1H), 4.94 (t, J=1.4 Hz, 1H), 4.73 (dd, J=13.6, 1.2 Hz, 1H), 4.59 (dd, J=13.5, 1.5 Hz, 1H), 4.18 (qd, J=7.1, 1.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 165.3, 163.1, 137.5, 135.1, 129.2, 128.8, 127.4, 122.2, 109.8, 87.2, 69.5, 59.9, 14.5.

LRMS (ESI) calculated for C₁₅H₁₆O₄ [M+H]⁺: 261.1. Found: 261.1.

Synthesis of Enol Acetate 3

To a solution of cinnamyl bromide (0.74 mL, 5.0 mmol) and 3-butyn-1-ol (0.45 mL, 6.0 mmol) in THF was added sodium hydride (60% dispersion in mineral oil, 300 mg, 7.5 mmol) at 0° C. The solution was stirred for 3 h at ambient temperature and then saturated NH₄Cl solution was added to quench the reaction, followed by addition of ethyl acetate. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:10) to give the homopropargylic cinnamyl ether as colorless oil (649.6 mg, 70% yield). (See Gudla, V.; Balamurugan, R. J. Org. Chem. 2011, 76, 9919).

To a mixture of [Ru(p-cymene)Cl₂]₂ (12.2 mg, 0.02 mmol), tri(2-furyl)phosphine (9.3 mg, 0.04 mmol), Na₂CO₃ (106.0 mg, 1.0 mmol), and the homopropargylic cinnamyl ether (37.3 mg, 0.2 mmol) in toluene (4.0 mL) was added acetic acid (0.57 mL, 10 mmol). The solution was stirred at 80° C. for 15 min and then a solution of the homopropargylic cinnamyl ether (335.3 mg, 1.8 mmol) in 1.0 mL toluene was added. The resulting solution was stirred at 80° C. for 20 h. The crude mixture was cooled to room temperature and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:10) to give the enol acetate 3 as colorless oil (286.8 mg, 77% yield). (See Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 1083).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39 (d, J=7.5 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.27-7.20 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.28 (dt, J=16.0, 6.0 Hz, 1H), 4.86-4.75 (m, 2H), 4.16 (dd, J=6.0, 1.5 Hz, 2H), 3.62 (t, J=6.6 Hz, 2H), 2.55 (t, J=6.6 Hz, 2H), 2.13 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 169.3, 153.6, 136.8, 132.6, 128.7, 127.8, 126.6, 126.1, 103.1, 71.6, 67.1, 34.1, 21.2.

HRMS (ESI) calculated for C1411803 [M+Na]⁺: 269.1154. Found: 269.1152.

CDC Reaction of Enol Acetate 3

To an oven dried 20 mL reaction vial equipped with a magnetic stir bar under N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 250 mg of 4 Å molecular sieve (powder), 1.0 mL of L3.Cu(OTf)₂ (0.02 M in CH₂Cl₂), and 4.0 mL of CH₂Cl₂. The solution then was stirred for 1 h. The enol acetate 3 was dissolved in 1.0 mL of CH₂Cl₂ and was added, and the solution stirred at ambient temperature for 30 minutes. The reaction was then cooled to −70° C., and DDQ (59.0 mg, 0.26 mmol) dissolved in 4.0 mL of DCM was added over 1 h by syringe pump. The reaction was stirred for 12 h at −70° C., and then 1.0 mL of Et₃N was added to quench the reaction. The solution was filtered over a pad of silica (4 cm) with ethyl acetate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the tetrahydropyran-4-ones 4 (27.5 mg, 68% yield, 50:50 e.r.).

CDC Reaction of Cinnamylmethyl Ether with Methyl 2-Acetoacetate

To an oven dried 20 mL reaction vial equipped with a magnetic stir bar under N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 250 mg of 4 Å molecular sieve (powder), 1.0 mL of L3.Cu(OTf)₂ (0.02 M in CH₂Cl₂), and 4.0 mL of CH₂Cl₂. The solution then was stirred for 1 h. The cinnamylmethyl ether and methyl 2-acetoacetate were dissolved in 1.0 mL of CH₂Cl₂ and was added, and the solution stirred at ambient temperature for 30 minutes. The reaction was then cooled to −70° C., and DDQ (59.0 mg, 0.26 mmol) dissolved in 4.0 mL of DCM was added over 1 h by syringe pump. The reaction was stirred for 12 h at −70° C., and then 1.0 mL of Et₃N was added to quench the reaction. The solution was filtered over a pad of silica (4 cm) with ethyl acetate and concentrated under reduced pressure (During concentration of solvents, the desired coupling product was converted to the conjugated enones). The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:5) to give the conjugated enones (35.9 mg, 78% yield, E/Z=2.7:1). (See Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron. Lett. 1999, 40, 4129).

5. Transformation of Tetrahydropyran-4-One 2a

To a 5 mL reaction vial equipped with a magnetic stir bar was added the 2a (26.0 mg, 0.1 mmol, 95:5 e.r.), 0.5 mL of DMF, and 20 μL of H₂O. The solution then was stirred for 5 h at 130° C. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the tetrahydropyran-4-one 4 as white solid (15.5 mg, 77% yield, 95:5 e.r.). (See Reddy, B. V. S.; Anjum, S. R.; Sridhar, B. RSC Adv. 2016, 6, 75133).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.29-7.24 (m, 2H), 7.23-7.17 (m, 2H), 7.16-7.10 (m, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.10 (dd, J=16.0, 5.9 Hz, 1H), 4.35-4.13 (m, 2H), 3.66 (td, J=11.8, 3.0 Hz, 1H), 2.57-2.48 (m, 1H), 2.47-2.36 (m, 2H), 2.31-2.20 (m, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 206.3, 136.3, 131.8, 128.7, 128.2, 128.1, 126.7, 78.3, 66.4, 48.3, 42.3.

Chiral SFC (Chiralpak IB-3, 3% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.1 min (major), 2.8 min (minor).

To an oven dried 5 mL reaction vial equipped with a magnetic stir bar was added the 2a (26.0 mg, 0.1 mmol, 95:5 e.r.), 4.8 mg of NaH (60% in oil, 0.12 mmol), and 1.0 mL of THF at 0° C. Methyl iodide (24.9 μL, 0.4 mmol) was added to the solution. The solution was stirred for 1 h at 0° C. and then stirred for 16 h at ambient temperature additionally. The saturated NH₄C1 solution was added to quench the reaction, followed by addition of ethyl acetate. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the methylated tetrahydropyran-4-one 7 as colorless oil (26.5 mg, 97% yield, 95:5 e.r., 13:1 d.r.). The stereochemistry of the product was determined by NOESY experiments (data not shown).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.43-7.39 (m, 2H), 7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H), 6.63 (d, J=15.9 Hz, 1H), 6.49 (dd, J=15.9, 7.1 Hz, 1H), 4.39 (ddd, J=11.4, 8.1, 1.1 Hz, 1H), 3.89 (dd, J=7.2, 1.0 Hz, 1H), 3.85-3.78 (m, 1H), 3.73 (s, 3H), 3.22 (ddd, J=14.8, 12.7, 8.1 Hz, 1H), 2.48 (ddd, J=14.8, 3.1, 1.1 Hz, 1H), 1.32 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 203.6, 170.5, 136.4, 134.0, 128.7, 128.2, 126.9, 124.5, 86.8, 67.4, 62.2, 52.6, 41.1, 16.2.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1110.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.4 min (major), 2.2 min (minor) for (2R,3S)-7 and 3.0 min (major), 5.7 min (minor) for (2R,3R)-7.

To an oven dried 5 mL reaction vial equipped with a magnetic stir bar was added the corresponding tetrahydropyran-4-one (0.1 mmol, 95:5 e.r.), and 2.0 mL of THF at −70° C. The L-selectride (0.3 mL, 1.0 M in THF) was slowly added to the solution. The solution was stirred for 3 h at −70° C. and then quenched with saturated NH₄C1 solution. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:2) to give the corresponding tetrahydropyran-4-ol.

White solid (16.8 mg, 64% yield, 95:5 e.r.)

¹H NMR (500 MHz, C₆D₆): δ ppm 7.24-7.20 (m, 2H), 7.09-7.04 (m, 2H), 7.03-6.98 (m, 1H), 6.69 (d, J=15.9 Hz, 1H), 6.32 (dd, J=16.0, 6.8 Hz, 1H), 4.73 (dd, J=10.1, 6.8 Hz, 1H), 4.14-3.97 (m, 2H), 3.67 (ddd, J=11.3, 4.8, 2.0 Hz, 1H), 3.47 (s, 1H), 3.15 (s, 3H), 2.54 (dd, J=10.3, 2.2 Hz, 1H), 1.52-1.40 (m, 2H).

¹³C NMR (125 MHz, C₆D₆): δ ppm 174.0, 137.3, 132.1, 128.8, 128.7, 128.4, 126.9, 74.2, 64.7, 62.2, 52.6, 51.3, 31.9.

HRMS (ESI) calculated for C₁₅H₁₈O₄ [M+Na]⁺: 285.1103. Found: 285.1108.

Chiral SFC (Chiralpak IC-3, 5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.7 min (major), 3.4 min (minor).

Colorless oil (19.6 mg, 71% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.36-7.30 (m, 2H), 7.26 (dd, J=8.4, 6.8 Hz, 2H), 7.21-7.17 (m, 1H), 6.52 (d, J=15.9 Hz, 1H), 6.37 (dd, J=15.9, 7.1 Hz, 1H), 4.08 (ddd, J=11.7, 5.3, 2.1 Hz, 1H), 3.68 (s, 3H), 3.62 (d, J=7.6 Hz, 1H), 3.55 (td, J=11.8, 2.9 Hz, 1H), 3.49 (td, J=10.7, 4.8 Hz, 1H), 3.02 (d, J=10.0 Hz, 1H), 2.20-2.08 (m, 1H), 1.93-1.81 (m, 1H), 1.30 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 174.9, 136.9, 132.9, 128.7, 127.9, 126.8, 125.9, 85.1, 75.4, 66.6, 52.5, 52.0, 32.6, 19.8.

HRMS (ESI) calculated for C₁₆H₂₀O₄[M+Na]⁺: 299.1259. Found: 299.1266.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 9.0 min (major), 7.7 min (minor).

To an oven dried 5 mL reaction vial equipped with a magnetic stir bar was added LiAlH₄ (19.0 mg, 0.5 mmol), and 3.0 mL of THF at 0° C. The 7 (27.4 mg, 0.1 mmol, 95:5 e.r.) dissolved in 2.0 mL of THF was added slowly and then the solution was stirred for 5 h at 0° C. The saturated Rochelle salt solution was added to quench the reaction, followed by addition of ethyl acetate. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:1) to give the dialcohol 10 as colorless oil (15.4 mg, 62% yield, 95:5 e.r.).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39-7.35 (m, 2H), 7.31 (dd, J=8.5, 6.7 Hz, 2H), 7.27-7.22 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.17 (dd, J=15.9, 6.3 Hz, 1H), 4.28 (d, J=11.1 Hz, 1H), 4.14 (ddd, J=11.7, 5.3, 1.5 Hz, 1H), 3.73-3.63 (m, 3H), 3.59 (td, J=12.6, 2.6 Hz, 1H), 3.22 (s, 1H), 2.58 (s, 1H), 2.14 (qd, J=12.8, 5.3 Hz, 1H), 1.91-1.85 (m, 1H), 1.18 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 136.7, 132.6, 128.7, 127.9, 126.6, 124.9, 85.0, 77.3, 67.0, 65.0, 43.0, 32.5, 18.8.

HRMS (ESI) calculated for C₁₅H₂₀O₃[M+Na]⁺: 271.1310. Found: 271.1315.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.6 min (major), 4.4 min (minor).

To a 50 mL round bottom flask equipped with a magnetic stir bar was added 33.2 mg of Pd(TFA)₂ (0.1 mmol), and the 7 (274.3 mg, 1.0 mmol, 93:7 e.r.). The flask was purged and filled with O₂ three times and then an oxygen balloon was attached via a needle. 10 mL of DMSO bubbled with O₂ and the solution was stirred for 2 days at 80° C. Once O₂ was vented, water was added to the solution, followed by addition of diethyl ether. The aqueous layer was extracted with diethyl ether, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the cyclic enone 11 as pale yellow solid (182.4 mg, 67% yield, 93:7 e.r.). (Starting material 7 was hardly separated from product 11 by column chromatography. Therefore, the reaction should be terminated after the 7 is completely consumed. If the reaction does not give full conversion, the reaction can be performed again with crude mixture after workup process.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.42 (m, 3H), 7.38-7.34 (m, 2H), 7.33-7.29 (m, 1H), 6.76 (d, J=15.9 Hz, 1H), 6.49 (dd, J=15.9, 8.1 Hz, 1H), 5.58 (d, J=6.0 Hz, 1H), 4.70 (d, J=8.1 Hz, 1H), 3.72 (s, 3H), 1.39 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 190.1, 169.8, 163.1, 137.0, 135.7, 128.9, 128.8, 127.1, 121.9, 106.8, 86.7, 55.7, 52.8, 16.7.

HRMS (ESI) calculated for C₁₆H₁₆O₄[M+Na]⁺: 295.0946. Found: 295.0951.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 5.5 min (major), 2.5 min (minor).

A 10 mL flask was flushed with nitrogen and charged with Rh(cod)₂BF₄ (4.1 mg, 0.01 mmol), 0.1 mL of degassed H₂O, and 2.0 mL of degassed dioxane. Phenylboronic acid (36.6 mg, 0.3 mmol) and the 11 (27.2 mg, 0.1 mmol, 93:7 e.r.) were added to the solution. After being stirred at 100° C. for 12 h, the reaction mixture was passed through a pad of silica gel with ethyl acetate and the solvent was removed under vacuum. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the tetrahydropyran-4-one 12 as colorless oil (26.3 mg, 75% yield, 93:7 e.r.). The stereochemistry was assigned trans configuration between C2-H and C6-H based on ¹H NMR data reported in the literature. (See (a) Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Jagadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468. (b) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Maddaford, S. P. Org. Lett. 2001, 3, 2571).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.28-7.23 (m, 5H), 7.21-7.16 (m, 3H), 7.15-7.10 (m, 2H), 6.38 (d, J=15.9 Hz, 1H), 6.28 (dd, J=15.9, 6.8 Hz, 1H), 5.43 (dd, J=7.4, 3.1 Hz, 1H), 3.93 (d, J=6.8 Hz, 1H), 3.63 (s, 3H), 3.35 (dd, J=15.4, 7.5 Hz, 1H), 2.99 (dd, J=15.4, 3.1 Hz, 1H), 1.13 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.3, 170.6, 139.4, 136.4, 133.7, 128.9, 128.7, 128.4, 128.2, 127.3, 126.9, 124.4, 78.8, 74.8, 61.5, 52.7, 42.5, 16.6.

HRMS (ESI) calculated for C₂₂H₂₂O₄ [M+Na]⁺: 373.1416. Found: 373.1430.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 1.7 min (major), 2.0 min (minor).

To an oven dried 10 mL vial equipped with a magnetic stir bar was added 38.1 mg of CuI (0.2 mmol), THF (1.5 mL) and n-BuLi (0.16 mL, 2.5 M in Hexanes) at 0° C. After being stirred for 20 min, the solution was cooled to −78° C. and then TMSCl (76 μl, 0.6 mmol) was added to the solution. The 11 (27.2 mg, 0.1 mmol, 93:7 e.r.) dissolved in 1.5 mL of THF was added slowly. The solution was stirred for 2.5 h at −78° C. and then quenched with saturated NH₄C1 solution. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the tetrahydropyran-4-one 13 as colorless oil (25.0 mg, 76% yield, 93:7 e.r.). The trans stereochemistry of the product was determined by NOESY experiments (data not shown).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.41 (d, J=7.3 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.28-7.23 (m, 1H), 6.62 (d, J=15.9 Hz, 1H), 6.46 (dd, J=15.9, 7.2 Hz, 1H), 4.46-4.33 (m, 1H), 4.21 (d, J=7.1 Hz, 1H), 3.72 (s, 3H), 3.18 (dd, J=14.7, 7.0 Hz, 1H), 2.44 (dd, J=14.7, 3.5 Hz, 1H), 1.78-1.65 (m, 1H), 1.51-1.41 (m, 1H), 1.42-1.30 (m, 7H), 0.90 (td, J=5.6, 4.3, 1.7 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.6, 170.6, 136.5, 133.7, 128.7, 128.2, 126.9, 124.9, 78.7, 73.8, 61.5, 52.6, 44.3, 32.9, 27.7, 22.5, 16.9, 14.1.

HRMS (ESI) calculated for C₂₀H₂₆O₄[M+Na]⁺: 353.1729. Found: 353.1744.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 3.8 min (major), 1.8 min (minor).

To an oven dried 10 mL vial equipped with a magnetic stir bar was added 2.2 mg of InCl₃ (0.01 mmol), the 11 (27.2 mg, 0.1 mmol, 93:7 e.r.), and CH₂Cl₂ (1 mL) at −78° C. Silyl enol ether (57.7 mg, 0.3 mmol) dissolved in 0.5 mL of CH₂Cl₂ was added slowly and then the solution was stirred for 4 h at −78° C. After warm up to 0° C., saturated KF solution was added and then stirred for 1 h at ambient temperature. The aqueous layer was extracted with ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography with ethyl acetate/hexane (1:4) to give the tetrahydropyran-4-one 14 as colorless oil (36.5 mg, 93% yield, 93:7 e.r., 10:1 d.r.). The trans stereochemistry of the product was determined by NOESY experiments (data not shown).

¹H NMR (500 MHz, CDCl₃): δ ppm 8.01-7.89 (m, 2H), 7.61-7.55 (m, 1H), 7.50-7.43 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 2H), 7.28-7.23 (m, 1H), 6.56 (d, J=15.9 Hz, 1H), 6.41 (dd, J=15.8, 7.3 Hz, 1H), 5.07 (p, J=6.1, 5.5 Hz, 1H), 4.36 (d, J=7.2 Hz, 1H), 3.73 (s, 3H), 3.38 (dd, J=16.3, 5.6 Hz, 1H), 3.26 (ddd, J=15.4, 12.8, 7.2 Hz, 2H), 2.66 (dd, J=15.3, 4.9 Hz, 1H), 1.37 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.2, 197.1, 170.5, 136.8, 136.3, 134.3, 133.7, 128.9, 128.7, 128.3, 126.9, 124.2, 80.2, 70.4, 61.4, 52.7, 43.6, 42.7, 17.2.

HRMS (ESI) calculated for C₂₄H₂₄O₅ [M+Na]⁺: 415.1521. Found: 415.1529.

Chiral SFC (Chiralpak IC-3, 5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250 nm): 8.8 min (major), 8.2 min (minor).

Stereochemical Models

The initial geometry of L3.Cu(II)(H₂O)₂ was based on the X-ray crystal structure of [L1.Cu(H₂O)₂](SbF₆)₂ in the literature. (See Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635). Dihedral angles were fixed for optimization (as shown below). Geometry optimization of L3.Cu(II) with 1a/DDQ intermediate (FIG. 3 ) was performed using the PM3 optimized structure of L3.Cu(II)(H₂O)₂ (FIG. 4 ). C1′-C2′ length was fixed to 2.2 Å.

Photoredox-Catalyzed CDC Reaction of 1a

To an over dried 25 mL round bottom flask equipped with a magnetic stir bar was charged with 1a (52.5 mg, 0.2 mmol), BrCCl₃ (39 μl, 0.4 mmol), 150 mg 4 Å MS, Sc(OTf)₃ (9.8 mg, 0.02 mmol), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]PF₆, (2.2 mg, 0.002 mmol), 2 mL of degassed CH₂Cl₂ was added to the flask, and the mixture was then irradiated by blue LED lamps under an atmosphere of Ar for 24 h. After the reaction was complete the mixture was poured into a separator y funnel containing 15 mL of ethyl acetate and 10 mL of H₂O. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×15 mi.). The combined organic layers were dried and concentrated in vacuo. The crude was purified by silica gel column chromatography to afford product 2a as the sole diastereomer (46.9 mg, 90% yield).

Crystal Structure of 2h.

X-ray quality crystals for 2h were obtained by slow diffusion in benzene/hexanes at r

Empirical formula C₁₅H₁₅N₄Br Formula weight 339.18 Temperature 99.95 K Crystal system monoclinic Space group P2₁ Unit cell dimensions a = 8.7786(8) Å α = 90°. b = 8.2454(7) Å β = 110.205(4)°. c = 10.7228(9) Å γ = 90°. Volume 728,39(11) Å³ Z 2 Density (calculated) 1.546 Mg/m³ Absorption coefficient 2,831 mm⁻¹ F(000) 344 Crystal size 0.117 × 0.074 × 0.048 mm³ 2Θ range for data 4,048 to 77.302°. collection Index ranges −15 <= h <= 15, −14 <= k <= 14, −18 <= 1 <= 18 Reflections collected 54501 Independent reflections 8255 [R(int) = 0.0360] Data/restraints/parameters 8755/1/182 Goodness-of-fit on F2 1.037 Final R indices R₁ = 0.0268, [I>2sigma(I)] wR₂ = 0.0635 R indices (all data) R₂ = 0.0341, wR₂ = 0.0662 Largest cliff peak 0.723 and -0.503 e•Å⁻³ and hole

REFERENCES

-   (1) (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362; (b)     Marmsater, F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4346-4353. -   (2) (a) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 1977,     661-672; (b) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc.     1999, 121, 1092-1093; (c) Jasti, R.; Vitale, J.;     Rychnovsky, S. D. J. Am. Chem. Soc. 2004, 126, 9904-9905. -   (3) (a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew.     Chem. Int. Ed. 1999, 38, 2398-2400; (b) Heravi, M. M.; Ahmadi, T.;     Ghavidel, M.; Heidari, B.; Hamidi, H. RSC Advances 2015, 5,     101999-102075. -   (4) (a) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2006,     2045-2053; (b) Larrosa, I.; Romea, P.; Urpi, F. Tetrahedron 2008,     64, 2683-2723. -   (5) (a) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 37,     1218-1228; (b) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2012, 41,     988-999. -   (6) Vetica, F.; Chauhan, P.; Dochain, S.; Enders, D. Chem. Soc. Rev.     2017, 46, 1661-1674. -   (7) (a) Betori, R. C.; Miller, E. R.; Scheidt, K. A. Adv. Synth.     Catal. 2017, 359, 1131-1137; (b) Morris, W. J.; Custar, D. W.;     Scheidt, K. A. Org. Lett. 2005, 7, 1113-1116; (c) Wang, J.;     Crane, E. A.; Scheidt, K. A. Org. Lett. 2011, 13, 3086-3089. -   (8) Crane, E. A.; Zabawa, T. P.; Farmer, R. L.; Scheidt, K. A.     Angew. Chem. Int. Ed. 2011, 50, 9112-9115. -   (9) (a) Custar, D. W.; Zabawa, T. P.; Hines, J.; Crews, C. M.;     Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 12406-12414; (b)     Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc. 2008,     130, 804-805. -   (10) Tenenbaum, J. M.; Morris, W. J.; Custar, D. W.; Scheidt, K. A.     Angew. Chem. Int. Ed. 2011, 50, 5892-5895. -   (11) (a) Lee, K.; Kim, H.; Hong, J. Org. Lett. 2011, 13,     2722-2725; (b) Lee, K.; Kim, H.; Hong, J. Angew. Chem. Int. Ed.     2012, 51, 5735-5738; (c) Han, X.; Peh, G.; Floreancig, P. E. Eur. J.     Org. Chem. 2013, 2013, 1193-1208; (d) Nasir, N. M.; Ermanis, K.;     Clarke, P. A. Org. Biomol. Chem. 2014, 12, 3323-3335. -   (12) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335-344; (b) Yeung, C.     S.; Dong, V. M. Chem. Rev. 2011, 111, 1215-1292; (c) Girard, S. A.;     Knauber, T.; Li, C.-J. Angew. Chem. Int. Ed. 2014, 53, 74-100. -   (13) (a) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A.     K.; Lei, A. Chem. Rev. 2017, 117, 9016-9085; (b) Davies, H. M. L.;     Morton, D. J. Org. Chem. 2016, 81, 343-350; (c) Gensch, T.;     Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev.     2016, 45, 2900-2936; (d) Arockiam, P. B.; Bruneau, C.;     Dixneuf, P. H. Chem. Rev. 2012, 112, 5879-5918; (e) Colby, D. A.;     Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45,     814-825; (f) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011,     40, 1976-1991; (g) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,     110, 1147-1169. -   (14) (a) Ying, B.-P.; Trogden, B. G.; Kohlman, D. T.; Liang, S. X.;     Xu, Y.-C. Org. Lett. 2004, 6, 1523-1526; (b) Zhang, Y.; Li, C.-J.     Angew. Chem. Int. Ed. 2006, 45, 1949-1952. -   (15) (a) Brizgys, G. J.; Jung, H. H.; Floreancig, P. E. Chem. Sci.     2012, 3, 438-442; (b) Cui, Y.; Floreancig, P. E. Org. Lett. 2012,     14, 1720-1723; (c) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11,     3152-3155; (d) Liu, L.; Floreancig, P. E. Angew. Chem. Int. Ed.     2010, 49, 5894-5897; (e) Tu, W.; Liu, L.; Floreancig, P. E. Angew.     Chem. Int. Ed. 2008, 47, 4184-4187. -   (16) (a) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Angew. Chem.     Int. Ed. 2010, 49, 5558-5562; (b) Zhang, G.; Zhang, Y.; Wang, R.     Angew. Chem. Int. Ed. 2011, 50, 10429-10432; (c) Zhang, J.; Tiwari,     B.; Xing, C.; Chen, X.; Chi, Y. R. Angew. Chem. Int. Ed. 2012, 51,     3649-3652; (d) Tan, Y.; Yuan, W.; Gong, L.; Meggers, E. Angew. Chem.     Int. Ed. 2015, 54, 13045-13048; (e) Yang, Q.; Zhang, L.; Ye, C.;     Luo, S.; Wu, L.-Z.; Tung, C.-H. Angew. Chem. Int. Ed. 2017, 56,     3694-3698. -   (17) (a) Cui, Y.; Villafane, L. A.; Clausen, D. J.;     Floreancig, P. E. Tetrahedron 2013, 69, 7618-7626; (b) Meng, Z.;     Sun, S.; Yuan, H.; Lou, H.; Liu, L. Angew. Chem. Int. Ed. 2014, 53,     543-547. -   (18) CCDC 1817530 (2h) contains the supplementary crystallographic     data. See Supp. Info. for details. -   (19) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J.     Am. Chem. Soc. 2001, 123, 4480-4491. -   (20) Clarke, P. A.; Sellars, P. B.; Nasir, N. M. Org. Biomol. Chem.     2015, 13, 4743-4750. -   (21) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133,     14566-14569. -   (22) The relative stereochemistry of 12 was assigned trans     con-figuration between C2-H and C6-H based on data reported in the     literature. See: (a) Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.;     Jagadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468-8471; (b)     Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.;     Maddaford, S. P. Org. Lett. 2001, 3, 2571-2573. -   (23) The trans stereochemistry of the products was determined by     NOESY experiments. See Figure S1 and S2 in Supp. Info. for details. -   (24) Chua, S.-S.; Alni, A.; Jocelyn Chan, L.-T.; Yamane, M.; Loh,     T.-P. Tetrahedron 2011, 67, 5079-5082. -   (25) (a) Carpenter, J.; Northrup, A. B.; Chung, d.; Wiener, J. J.     M.; Kim, S.-G.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2008, 47,     3568-3572; (b) Smith, A. B.; Tomioka, T.; Risatti, C. A.; Sperry, J.     B.; Sfouggatakis, C. Org. Lett. 2008, 10, 4359-4362; (c) Olier, C.;     Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2010, 66,     413-445. -   (26) (a) Ferrié, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org.     Lett. 2007, 9, 2461-2464; (b) Brazeau, J.-F.; Guilbault, A.-A.;     Kochuparampil, J.; Mochirian, P.; Guindon, Y. Org. Lett. 2010, 12,     36-39. -   (27) Tucker, J. W.; Narayanam, J. M. R.; Shah, P. S.;     Stephenson, C. R. J. Chem. Commun. 2011, 47, 5040-5042. -   (28) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116,     10035. -   (29) Pangborn, A. B.; Giardelo, M. A.; Grubbs, R. H.; Rosen, R. K.;     Timmers, F. J. Organometallics 1996, 15, 1518. -   (30) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.;     Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541. -   (40) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209. -   (41) Krishna, T. R.; Jayaraman, N, J. Org. Chem. 2003, 68, 9694. -   (42) Gudla, V.; Balamurugan, R. J. Org. Chem. 2011, 76, 9919. -   (43) Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 1083. -   (44) Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron.     Lett. 1999, 40, 4129. -   (45) Reddy, B. V. S.; Anjum, S. R.; Sridhar, B. RSC Adv. 2016, 6,     75133. -   (46) (a) Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Jagadeesh,     B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468. (b) Ramnauth, J.;     Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Maddaford, S. P. Org.     Lett. 2001, 3, 2571. -   (47) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc.     2000, 122, 1635. -   (48) Wan et al., “Organocatalytic Redox Deracemization of Cyclic     Benzylic Ethers Enabled by An Acetal Pool Strategy,” Angew. Chem.     Int. Ed. Engl. 2017, 56(18):5116-5120. -   (49) Lu et al., “Redox deracemization of     1,3,4,9-tetrahydropyrano[3,4-b]indoles,” Chem. Commun. 2018, 54,     4445-4448.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been illustrated by specific embodiments and optional features, modification and/or variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

Citations to a number of patent and non-patent references are made herein. The cited references are incorporated by reference herein in their entireties. In the event that there is an inconsistency between a definition of a term in the specification as compared to a definition of the term in a cited reference, the term should be interpreted based on the definition in the specification. 

We claim:
 1. A complex having a formula represented as L.M²⁺(OTf)₂, wherein M is a divalent metal, Tf is triflyl, and L has a formula:

wherein R⁸ and R⁹ together form a 3-membered, 4-membered, 5-membered, or 6-membered carbocyclic ring; and R¹⁰ and R¹¹ are alkyl.
 2. The complex of claim 1, wherein L has a formula:


3. The complex of claim 1, wherein L has a formula:


4. The complex of claim 1, wherein L has a formula:


5. The complex of claim 1, wherein L has a formula: 